Atrial Fibrillation

Atrial Fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia that requires treatment, with an estimated prevalence in the United States of 3 to 6 million.1 Its prevalence increases with age, hypertension, and heart failure: 3–4% of patients aged 65–75 have AF and 10% of patients aged 80 years or older have AF; 4% of patients with heart failure (HF) functional class I and 50% of patients with functional class IV have AF.2 On the other hand, HF is present in 34% of AF patients.3 AF is typically initiated by one or more premature atrial complexes, often originating around the pulmonary veins, or by atrial tachycardia or atrial flutter.

I. Predisposing factors (see Table 10.1)

Hypertension is the most common factor associated with AF on a population basis; coronary artery disease (CAD) and HF are the most common associated features in hospital series.4 Between 30% and 45% of paroxysmal AF cases, and 20–25% of persistent AF cases, are “lone AF,” i.e., AF that occurs in patients younger than 65 years without underlying heart or lung disease and without hypertension.5 Even in the case of lone AF, there are structural atrial abnormalities and some degree of atrial dilatation and dysfunction, as well as an increased prevalence of high-normal blood pressure (i.e., systolic pressure 130–140 mmHg), that are contributive to AF.6,7 As they age, however, patients with lone AF may develop hypertension or heart disease that contributes to the progression of AF.

The most frequent histopathological feature of AF is atrial fibrosis, which may precede the onset of AF. Atrial dilatation is present in over 50% of patients with AF, with a mean left atrial diameter of ~40 ± 8 mm in the Canadian Registry of non-valvular AF; atrial dilatation is less prevalent in patients with non-recurrent AF and lone AF.7 Atrial dilatation may be not only a cause but also a consequence of AF, as evidenced by the fact that the left atrial size further increases with time, over months to years, in patients with persistent AF.8,9 On the other hand, left atrial size decreases after AF cardioversion.10,11 Atrial electrical remodeling, i.e., progressive shortening of the effective refractory period, further explains how prolonged AF makes restoring and maintaining sinus rhythm less likely (“AF begets AF”).2

Table 10.1 Factors predisposing to atrial fibrillation.

  • Systemic arterial hypertension
  • Coronary artery disease
  • Heart failure
  • Any acute or chronic structural heart disease
  • Obesity and sleep apneaa
  • Atrial inflammation: pericarditis, myocarditis
  • Metabolic disorders: alcohol, hyperthyroidism, hypokalemia
  • Pulmonary diseases: COPD, pulmonary embolism
  • Postoperative state (cardiac, pulmonary, or esophageal surgeries)

a Sleep apnea is seen in >40% of patients with AF. Yet, CPAP did not reduce AF burden in the A3 randomized trial.

AF requires a trigger that initiates the arrhythmia and a substrate that sustains it. The most common triggers are premature atrial beats originating from the pulmonary veins. Atrial stretch and atrial fibrosis shorten the atrial effective refractory period and disrupt the electrical interconnections between the muscle bundles, causing local conduction heterogeneity. This allows ectopic activity originating from the pulmonary veins or elsewhere to get conducted and initiate multiple microreentry cycles (atrial wavelets). Those microreentrant cycles collide like “tornadoes” and generate new tornadoes that propagate throughout the atria.

The autonomic system may contribute to the initiation of AF, i.e., an increase in the sympathetic or parasympathetic drive may trigger ectopy in the pulmonary veins and AF. Conversely, low level vagal stimulation, below the bradycardia threshold, may reduce AF burden.

II. Types of AF

There are three types of AF: paroxysmal, persistent, and permanent:2,12

  • Paroxysmal AF is defined as AF that terminates spontaneously in less than 7 days (often 24–48 hours). AF that is terminated with cardio- version at ≤7 days of onset is also considered paroxysmal AF in the most recent classification.
  • Persistent AF is AF that persists over 7 days or requires cardioversion at >7 days (or unknown duration). Long-standing persistent AF is continuous AF that persists greater than 12 months, yet the adoption of a rhythm-control strategy is still planned.
  • AF is considered permanent in cases of failure of cardioversion attempts, early recurrences after cardioversion, or decision not to cardiovert. A decision may be made not to cardiovert a patient who is asymptomatic after rate control and has a high likelihood of recurrence (e.g., longstanding AF of over a year or severe left atrial enlargement >5 cm).

Paroxysmal and persistent AF may be recurrent. Over time, patients may alternate between paroxysmal and persistent AF. For example, in a particular patient, most of the AF episodes may be self-terminating, while some of them may require cardioversion. While a paroxysmal AF may recur as paroxysmal AF for years, AF is generally progressive over time, with a rate of progression to persistent or permanent AF of ~15% within the first year.

The term “acute AF” is applied for acutely symptomatic, new AF or recurrent AF. It is a form of paroxysmal or early persistent AF. This is different from the term “newly diagnosed AF” (or first-detected AF) which is often acute and symptomatic but not necessarily; 21% of patients in whom AF is newly diagnosed are asymptomatic, and AF is diagnosed by routine pulse exam during an office visit.13 In the latter patients, AF is likely several weeks, months, or years old, and may be long-term persistent or permanent.

The term “valvular AF” is used to describe AF associated with mitral stenosis, or mechanical prosthetic heart valve, and portends a higher stroke risk than non-valvular AF. AF with a bioprosthetic valve or severe valvular disease that is not MS is not called valvular AF (ACC guidelines 2019).

III. General therapy of AF

There are four main consequences of AF: (i) thrombus formation in the left atrial appendage (LAA) followed by thrombus embolization,

(ii) fast heart rate which leads to compromised ventricular filling, (iii) loss of the atrial kick that contributes to up to 40% of the cardiac output in stable HF patients, (iv) rhythm irregularity, per se, reduces cardiac output compared to a similar rate that is regular. Also, a rapid ventricular response of ≥110 beats per minute that persists for over 2 weeks can cause tachycardia-mediated cardiomyopathy and HF.

A. Anticoagulation

Administer an anticoagulant regardless of whether AF is paroxysmal or permanent. AF often recurs, and asymptomatic recurrences are 12 times more common than symptomatic recurrences.14 In the AFFIRM study, the risk of ischemic stroke was strongly related to absent or suboptimal anticoagulation even in the rhythm-control strategy.15 Drug therapy makes AF recurrences shorter and slower, hence less symptomatic; the stroke risk, however, persists.

B. Rate control

Three classes of drugs may be used: β-blockers, non-dihydropyridine calcium channel blockers (CCBs) (diltiazem or verapamil), and digoxin.

β-blockers are effective as monotherapy in up to 70% of patients with AF,16 and are first-line therapy in compensated systolic HF. They also have an antiarrhythmic effect and may convert adrenergically mediated AF into sinus rhythm.

Digoxin is less effective for rate control during exertion. Digoxin is only used as monotherapy in decompensated systolic HF, when the acute initiation of β-blockers is not possible. Digoxin is effective in combination therapy: the combinations digoxin–β-blocker and digoxin–CCB are at least as effective and safe as the combination β-blocker–CCB.16

Two modern trials compared rate-controlling drugs:17 (i) RATAF compared monotherapy with CCBs vs. β-blockers; CCBs improved exercise capacity, symptoms, peak VO2, and NT-pro-BNP levels vs. β-blockers, despite a similar rate reduction. (ii)RATE-AF compared monotherapy with digoxin vs. bisoprolol (age ~75); digoxin improved functional class and NT-proBNP vs. bisoprolol, with a similar rate reduction and dramatically less adverse events and hospitalizations.

First-line treatment: CCB or β-blocker. Second-line: add digoxin or combine β-blocker + CCB. CCB is not an appropriate option in systolic HF. The combination of β-blocker and verapamil has a strong negative inotropic effect and should be avoided in all patients. Triple combination is required in ~15–20% of patients but increases the risk of excessive pauses. Pharmacological therapy can achieve rate control in >80% of patients.16 The remaining patients cannot be rate-controlled with drugs and require rhythm control, provided that long-term success can be expected, or failing that, atrioventricular nodal ablation with ventricular pacing. Patients with AF, including fast AF, may alternate with AF pauses, sinus pauses (immediately after AF converts to sinus rhythm), or sinus bradycardia; this limits the use of rate-controlling agents and requires tight rhythm control or pacemaker placement .

In symptomatic patients, the goal of therapy was to reduce heart rate to <80 bpm at rest, <110 bpm with moderate activity, and <100 bpm (average) on 24-hour Holter monitoring. This goal was adopted in the AFFIRM and RACE trials which established the efficacy of a rate-control strategy. However, in the RACE II trial, this strict rate control did not offer any benefit over a more lenient control (a resting heart rate <110 bpm at rest) in patients with permanent AF and mild or no AF-related symptoms.18 There was no significant difference in hard outcomes (death, hospitalization for HF, stroke) or in symptom control at 3-year follow-up. Note, however, that most patients in the lenient group had a heart rate <100 bpm (85 ± 14 bpm), which implies that 100 bpm may be a better lenient goal than 110 bpm.

Rate control in HF- A wealth of data indicates that strict rate control improves outcomes in systolic HF with sinus rhythm, but not in systolic HF with AF and not in HFpEF. A higher rate is necessary to compensate for the loss of atrial contribution to stoke volume; also, nocturnal pauses that accompany tight rate control may be particularly harmful in HF (induce VT, low flow). For AF associated with HF, the target rate control remains <100 bpm rather than <80 bpm (based on RACE-II substudy, substudies of β-blockers in HF, and Swedish HF registry).19 To improve HF outcomes, consider AF ablation rather than strict rate control.

C. Rhythm control

Rhythm control is generally the least important goal. Long-term rhythm control, as compared with rate control, did not reduce mortality, stroke rate, or HF hospitalizations in patients at high risk of stroke or AF recurrences (AFFIRM and RACE trials),20,21 and in stable HF patients with EF <35% (AF-CHF trial).22 In fact, rhythm control was associated with a higher rate of hospitalization for recurrent AF and drug-related brady- and tachy-arrhythmias. In addition, in the AFFIRM trial, rhythm control was associated with increased non-cardiac mortality, particularly when amiodarone was used (pulmonary and cancer mortality).23,24 Amiodarone was the most commonly used drug in the AFFIRM trial, while sotalol was the most commonly used drug in the RACE trial. These studies enrolled persistent AF (RACE), and paroxysmal or persistent AF (AFFIRM and AF CHF), and AF duration was mostly <1 year.

This failure of rhythm control was partly related to the withdrawal of anticoagulation, the marginal efficacy of antiarrhythmic drugs, and their toxicity: only 62% of patients in the rhythm-control arm of AFFIRM and 39% of the rhythm-control arm of RACE were in sinus rhythm on follow-up.21 Secondary analyses of these trials showed that the presence of sinus rhythm on follow-up was associated with improved quality of life (RACE)25 and survival (AFFIRM),23 regardless of the treatment strategy or the use of antiarrhythmic drugs. Antiarrhythmic drugs, per se, were associated with reduced survival.23

Conversely, modern trials have shown that a rhythm control strategy is superior in 2 settings: HF or, less dramatically, early AF (≤ 1 year, symptomatic or not, paroxysmal or persistent); as long as a safer and more effective rhythm control regimen is used, focused on AF ablation, over a background of anticoagulation and comprehensive risk factor management:

  • Compared to rate control or rhythm control with drugs, rhythm control with catheter ablation significantly and dramatically reduced both mortality and HF hospitalizations in systolic HF patients (CASTLE AF).26
  • Catheter ablation also showed a trend toward improvement in cardiovascular outcomes in all comers with AF, albeit modest (CABANA trial).27
  • In new AF ≤ 1 year, a stepwise rhythm control strategy focused on class Ic drugs (44%), dronedarone, AF ablation (20%), and less so, amiodarone (11–20%) slightly but significantly improved cardiovascular mortality by 0.3% per year, the overall cardiovascular outcomes by 1.1% per year, and stroke, compared to rate control. Sinus rhythm was maintained at 2 years in 82% of patients. This early AF control attenuates or reverses atrial cardiomyopathy.28 (EAST AFNET4 trial: mean age 70, median BMI 28, median AF duration 36 days, LA diameter 4.4 +/- 0.8 cm, asymptomatic AF in 30% of patients, first AF episode in 38%, paroxysmal AF in 36%, HF in 28%).
  • In ATHENA trial, dronedarone significantly reduced cardiovascular mortality (0.7%/yr), hospitalizations, and stroke compared to rate control.

In patients with BMI >27 kg/m2, weight loss >10%, by itself, dramatically reduces the recurrence of AF. Weight loss, by itself, is almost as effective as antiarrhythmic drugs in preventing AF recurrence, and it allows interruption of antiarrhythmic drugs in many patients (~50% freedom from AF and antiarrhythmic drugs over several years of follow-up, vs. <20% if no weight loss). Also, weight loss is synergistic with AF ablation and antiarrhythmic therapy (87% freedom from AF over several years of follow-up after ablation, vs. <40% if no weight loss). This is enhanced by aggressive control of HTN, diabetes, lipids, sleep apnea, and smoking (LEGACY and ARREST-AF studies).29,30

Table 10.2 Cases in which a rhythm-control strategy should be considered

  • Intolerable symptoms despite rate control (palpitations, functional limitation, or HF that correlates with AF episodes)
  • Difficulty in achieving rate control; or alternation of fast AF with sinus bradycardia, precluding the optimal use of rate-controlling drugs
  • Any HF, whether HFpEF, HFrEF, or RV failure, particularly if AF ablation can be done.26 This is even more important in decompensated HF (after stabilization and diuresis); or advanced, class III–IV HF (not well represented in the AF-CHF trial)
  • Newly diagnosed AF (≤1 year), even if symptoms get controlled with rate reduction (EAST-AFNET4 trial).a
  • EAST-AFNET4 recruited patients >65, but this is likely even more important in a young patient <65 (ESC class IIa) b 31
  • AF secondary to a treated precipitant (ischemia, hyperthyroidism)31

a 21% of patients in whom AF is newly diagnosed are asymptomatic; these patients are unlikely to benefit from a rhythm-control strategy.13

b Most patients in the AFFIRM and RACE trials were older than 65. A meta-analysis suggests that rhythm control may improve mortality in patients younger than 65.32

Table 10.3 Risk factors associated with failure of direct-current cardioversion, recurrence of AF after cardioversion, or progression of paroxysmal AF to persistent AF (first five are most important). The best candidate for rhythm control is the patient having Table 10.2criteria with none of Table 10.3criteria.

  • Severe left atrial enlargement, i.e., anteroposterior diameter >4.5–5 cm
  • AF duration of more than 1 year
  • Decompensated medical condition that has not been treated, including decompensated HF or hyperthyroidism
  • Previous recurrences of AF, especially ≥2 recurrences requiring cardioversion
  • Morbid obesity
  • Underlying structural heart disease (the more severe, the less likely rhythm control will succeed)
  • COPD
  • Age >75 years

The Euro Heart Survey developed a risk score, somewhat similar to CHADS2 score, that predicts the progression from paroxysmal to persistent or permanent AF: HAT2CH2 (Hypertension, Age >75, TIA or stroke 2 points, COPD, HF 2 points). HATCH score of 0 or 1 → <10% risk of progression; 2–5 → 25–30% risk of progression; 6 or 7 → 50% risk of progression at 1 year.33 Potentially harmful drugs and interventions, including cardioversion, may be avoided in a high HAT 2 CH 2 score.

IV. Management of a patient who presents with acute, symptomatic AF

  1. Direct-current cardioversion (DCCV) is indicated emergently in cases of severe shock, acute HF with severe pulmonary edema, or myocardial ischemia attributed to AF. Typically, to attribute severe hemodynamic compromise to AF and to justify urgent cardioversion, heart rate must be >150 bpm; or > 130 bpm in systolic HF. Look for potential causes of shock that might have triggered both hypotension and AF.
  2. Acute rate control is achieved with β-blockers or CCBs (= first-line agents) in the absence of hypotension or decompensated HF. These agents are given intravenously if AF is severely symptomatic, with an initial target <110 bpm (Table 10.4).

    • Intravenous digoxin or amiodarone is a first-line option in decompensated systolic HF or borderline low BP (ESC and ACC class I). Amiodarone has the theoretical risk of acutely cardioverting AF in a patient who may have an atrial appendage thrombus, but the short-term (24 hours) likelihood of cardioversion is low, particularly in HF or critical illness. Neither ACC nor ESC guidelines insist on this risk.
    • β-Blockers may be used acutely in low EF without clinical HF and in HFpEF.
    • The onset of action of IV drugs is fast (a few minutes), except for digoxin (1–5 hours).

  3. Acute AF often spontaneously resolves by 24 hours, in ~60% of the cases (70% at 48 hours), even more so in the absence of heart disease. Thus, a 24-hour wait-and-see strategy is reasonable.34 If AF persists beyond 24 hours:

    1. If a rhythm-control strategy is selected, perform acute cardioversion at 24 hours (DCCV or drugs), after TEE rules out left atrial appendage thrombus. The patient needs to receive acute anticoagulation with heparin, enoxaparin, or NOAC. Another option is to provide oral anticoagulation for 3 weeks then perform DCCV without TEE.

      Table 10.4 Dosage of the drugs used for acute rate control.

      1. Metoprolol 5 mg IV, to be repeated Q5 min up to 15 mg total. Then start oral metoprolol 25–50 mg Q6h if the IV doses prove effective and tolerated. The IV metoprolol effect lasts a few hours. Alternatively, esmolol IV drip may be given (short-acting; effect lasts 10–20 min after the drip is off). Esmolol is the preferred agent if it is uncertain whether β-blockers will be hemodynamically tolerated
      2. Diltiazem IV 0.25 mg/kg (~20 mg) bolus. May re-bolus with 0.35 mg/kg (~25 mg) in 15 min if no response to 20 mg, then start 5–15 mg/h IV drip in responders. The IV diltiazem effect lasts a few hours.a In comparison with β-blockers, diltiazem has:

        • more hypotensive effects in general (vasodilatation)
        • similar hypotensive effects in pre-shock, wherein BP depends on both the adrenergic and vascular tone
        • less negative inotropic effect (than verapamil as well), but still not advised in systolic HF

      3. Digoxin needs to be given as a load (0.5 mg, then 0.25 mg Q6–8 h × 2 = 1 mg load, oral or IV). The load is followed by 0.125–0.25 mg Qday

      Acute monotherapy with β-blockers or CCBs is effective in most cases, the target ventricular rate in the acute setting being usually 80–110 bpm (ESC). In case of total non-response to one agent, switch to another; in case of partial response to one, combine two agents, then try to wean off the first one. β-Blockers are more effective in hyperadrenergic states (e.g., postoperatively). Avoid digoxin as a sole agent to control the heart rate, except with decompensated heart failure or low blood pressure.

      a IV diltiazem may be used for a few hours, then oral diltiazem started 3 hours after discontinuation of the IV drip, with a daily oral dose equal to (mg/day): IV drip rate in mg/h x 30 + 30. Short-acting diltiazem may initially be used Q6h.

    2. Alternatively, for acute AF with symptoms <12–48 hours, immediate pharmacological cardioversion may be attempted with intravenous procainamide (30-min infusion, ~60% success rate, rare hypotensive effect) (RAFF2 trial); or oral flecainide load (300 mg, ~70% efficacy at 3–6 hours).34,35 This acute cardioversion allows early patient discharge.
    3. May allow the progression to a rate-controlled permanent AF. This depends on the severity of AF-related symptoms, their persistence despite rate control, the age of the patient (young → cardiovert), and the likelihood of AF recurrence.

  4. Hospitalize the patient with severe symptoms or HF. Also, hospitalize if DCCV is planned.
  5. Perform an echocardiogram and look clinically for underlying cardiac or systemic diseases: acute HF, MI, PE, bleeding, thyrotoxicosis. Correcting these factors (e.g., diuresis and vasodilators for HF) may control the rate and eventually convert AF to sinus rhythm. In fact, DCCV is often ineffective in the presence of uncontrolled triggers or uncontrolled HF, as AF quickly recurs after cardioversion.

V. Peri-cardioversion anticoagulation management

The risk of stroke in the peri-cardioversion period is ~8%, reduced to <0.5% with appropriate anticoagulation. For an AF episode that has lasted ≥48 hours:

  1. TEE or 3 weeks of anticoagulation is required before DCCV.
  2. Anticoagulation is required for at least 4 weeks after spontaneous or active cardioversion, regardless of whether the patient’s risk factors dictate long-term anticoagulant therapy.2 AF conversion to sinus rhythm is followed by a few weeks of atrial hypocontractility, during which a thrombus may form then embolize once the atria fully recover their contractility. If the patient does not have an indication for chronic anticoagulant therapy, administer an oral anticoagulant for 4 weeks only. If warfarin is initiated, bridging with LMWH is necessary during the critical first few days after cardioversion.

For acute AF<48 hours- Cardioversion of AF that has lasted <48 hours does not mandate TEE or oral anticoagulation before DCCV; heparin or one dose of LMWH is provided peri-cardioversion.2,31,36 The issue is, however, that AF may have been asymptomatic for some time before symptoms developed; symptoms may correspond to acceleration of AF rather than its onset. In addition, one study has found that as many as 4% of patients with AF <48 hours have LAA thrombus, particularly if underlying heart disease is present.37 A registry analysis found a stroke rate of ~1.1% after cardioversion of AF<48 hours, exclusively in patients with CHA2DS2-VAS ≥2.38 A Finnish study found a similar risk of 1.1% in patients with AF duration of 12–48 hours (cardioversion much safer at <12 hours).39 Thus a safe approach may be to perform TEE even if the presumed AF duration is <48 hours, except in patients with AF <12 hours or CHADS2-VAS of 0 or 1, as per ESC and Canadian guidelines, and to mandate 4 weeks of anticoagulation after DCCV even if AF <48 hours.31,40,41 ACC guidelines do not mandate TEE when AF is definitely <48 hours, regardless of thromboembolic risk factors (class IIa); ACC and ESC accept forgoing the 4 weeks of anticoagulation when AF <24 hours with CHADS2-VAS of 0 (class IIb).36

If the initial TEE shows LAA thrombus, anticoagulation should be given for at least 3 weeks, followed by a repeat TEE to document thrombus resolution before cardioversion. If thrombus persists, accept a rate-control strategy.31

VI. Antiarrhythmic management after the acute presentation

In 25% of patients, DCCV fails or AF recurs after a few seconds or minutes of sinus rhythm; in another 25%, AF recurs within 2 weeks. Distinguish DCCV failure from immediate recurrence: in failure, no sinus conversion occurs at any time, not even for a beat, whereas in immediate recurrence, one or few sinus beats are seen before recurrence of AF. Failure is treated with a higher DCCV energy, a change in pad position/defibrillation vector, IV ibutilide pretreatment, or by pushing down the pads over an obese chest to improve the energy penetration. Immediate or early recurrence may benefit from a second attempt at DCCV after preparation with an antiarrhythmic drug. Antiarrhythmic drugs reduce immediate recurrence but do not help with DCCV failure, as most of them actually increase the atrial defibrillation threshold (except ibutilide, sotalol and dronedarone).

The AF recurrence rate is 70–80% at 1 year after cardioversion. Even when antiarrhythmic agents are used, the recurrence rate is ~35–60% at 1 year (~half),42 this rate being higher in patients with multiple risk factors (Table 10.3).33,43 Except for lone AF, most patients with paroxysmal AF progress to persistent or permanent AF within a few years. This high failure rate underlines why a rate-control strategy is the most realistic strategy in patients with many risk factors for recurrence or progression, even more so if DCCV fails or if AF recurs within 2 weeks despite antiarrhythmic therapy. If a rhythm-control strategy is selected, antiarrhythmic therapy may be considered after a recurrence rather than the first episode in lower-risk patients, and a shorter antiarrhythmic duration is desirable, as most recurrences occur early on (e.g., 1 month of flecainide) (ESC guidelines);31 this may be followed by an as-needed, pill-in-the-pocket cardioversion of recurrences with flecainide.

The goal of a rhythm-control strategy is symptom control and quality of life improvement; thus, short and infrequent recurrences or mildly symptomatic recurrences of paroxysmal AF are not considered treatment failures in a patient who previously had severely symptomatic paroxysmal or persistent AF. Rate-slowing drugs should be continued throughout the rhythm-control approach to ensure adequate rate control during AF recurrences, unless the baseline sinus rate is slow.

Off-and-on, fast AF is typically more difficult to rate control than permanent AF, as slowing AF spells leads to excessive slowing of the baseline sinus rate; this AF frequently requires tight rhythm control, including catheter ablation, or pacemaker placement.

An alternative to antiarrhythmic therapy is catheter isolation of the pulmonary veins, which successfully prevents AF in 70% of the treated cases over 1 year of follow-up.2,12,44 It is indicated for the prevention of recurrent, symptomatic, paroxysmal or persistent AF, especially when the left atrial diameter is <4 cm, as second-line or even first-line therapy (Appendix 3).2,12 If it fails, thoracoscopic surgical ablation is a next option. As a last resort, AV nodal ablation with ventricular pacing may be required.

VII. Decisions about long-term anticoagulation, role of clopidogrel, role of triple therapy

A. Long-term anticoagulation

The annual risk of stroke in patients with AF not receiving any antithrombotic therapy ranges from 1% to 18%, and averages ~5% per year.45 The risk is increased in both paroxysmal and permanent AF, although less so if AF burden is low or if AF is paroxysmal, brief and infrequent (Section X). Two validated clinical schemes, CHADS2 and CHA2DS2-VAS scores, help predict this risk (Table 10.5).45 CHA2DS2-VAS improves the predictive value of CHADS2 and is particularly useful for further classifying a CHADS2 score of 0 or 1.31,46,47 In fact, some patients with CHADS2 score of 0 or 1 have a high stroke risk. For any level of CHADS2 score, warfarin reduces the stroke risk by 75% and increases major bleeding ~2.5-fold.48The absolute stroke reduction with warfarin only overcomes the bleeding risk when the stroke risk is ≥1.7% per year; the equipoise point is 0.9% with the non-vitamin K oral anticoagulants (NOACs).49 Aspirin has no effect on AF-induced stroke, and only reduces vascular-induced stroke by 21% while increasing major bleeding by 60%.2,31,48

In the ESC and ACC guidelines, no antithrombotic therapy (not even aspirin) is recommended for patients with a CHA2DS2-VAS score of 0 (not counting female sex), where the absolute stroke reduction with anticoagulation is marginal (≤0.5%), not justifying the bleeding risk. Anticoagulation is recommended for a score ≥2 (not counting female sex), and NOACs are recommended over warfarin. For a CHA2DS2-VAS score of 1 (not counting female sex), ACC and ESC guidelines suggest oral anticoagulation after assessment of bleeding risk (class IIa).2,31,36 In fact, for a score of 1, the benefit of anticoagulation is marginal, as the absolute stroke risk is 1.5–2% per year; the stroke reduction only slightly outweighs the bleeding risk. Anticoagulation is likely beneficial if the risk factor is age 65–74 (stroke risk ~3% per year), if the risk factor is severe (uncontrolled diabetes, severe HF), or if a NOAC is used.50 Aspirin is not indicated for AF purpose in any subgroup (ESC class III).

CHADS2 score does not apply to patients with valvular AF, who have a high stroke risk and require anticoagulation with warfarin regardless of the score. Warfarin is used in these patients, rather than NOACs. Also, regardless of CHADS2 score, patients with hypertrophic cardiomyopathy and AF have a high stroke risk that warrants anticoagulation.

Table 10.5 Stroke risk in patients with non-valvular atrial fibrillation not treated with anticoagulation.

CHADS2 score

CHA2DS2-VAS score
Yearly stroke risk according to CHADS2 scoreb Yearly stroke risk according to CHA2DS2-VAS scoreb
C: Congestive heart failurea 1 C: Congestive heart failure 1 0: 1.9%
Schematic illustration of three right arrows starting from the same point.
0: <1%
H: Hypertension 1 H: Hypertension 1 1: 2.8% 1: 1.5–2%
A: Age ≥75 1 A: Age ≥75 2 2: 4.0% 2: 2.5–3%
D: Diabetes 1 D: Diabetes 1 3: 5.9% 3: 3.2%
S: prior stroke or TIA 2 S: prior stroke or TIA 2 4: 8.5% 4: 4%
V: Vascular disease (CAD, PAD, aortic plaque) 1 5: 12.5% 5: ~7%
A: Age 65≥74 1 6: 18.2% 6–8: ~10%
S: Sex femalec 1 9: 15%

a “C” mandates either one of the following (ESC): (i) reduced EF, or (ii) documented HF decompensation, whether EF is reduced or normal (i.e., diastolic HF included).

b Numbers obtained from references 31 and 45.

c Female sex conveys increased risk only in patients who already have a high stroke risk, not in lower-risk patients with a non-sex related score of 0 or 1. Hence, female sex is only counted in patients with ≥2 non–sex-related risk factors. 36

B. Bleeding risk

Before starting anticoagulation or aspirin, the patient’s bleeding risk should be assessed. The HAS-BLED bleeding risk score may be used:51

H, hypertension; A, abnormal liver/kidneys; S, stroke; B, bleeding history; L, labile INR; E, elderly >65; D, drugs (antiplatelet drugs or NSAID) or alcohol

A score ≥3 implies a high bleeding risk and requires frequent evaluations of anticoagulation therapy (Table 10.6). A high HAS-BLED score warrants the correction of bleeding risk factors rather than the exclusion of anticoagulation (ESC guidelines). Five of the seven HAS-BLED risk factors are modifiable: control hypertension, address prior gastrointestinal bleed, switch to NOAC if labile INR, avoid alcohol and NSAIDs, correct acute renal dysfunction.31,52Patients with a high HAS-BLED score usually have a high CHA2DS2-VAS score and a high stroke risk, the absolute stroke risk increasing more sharply than the bleeding risk. Thus, these patients derive an even greater net clinical benefit from anticoagulation than patients with a low HAS-BLED score and should generally receive anticoagulation. 52,53 The bleeding risk is not only high with anticoagulation but may be as high with aspirin in those patients.54

Along the same lines, a patient receiving anticoagulation who develops gastrointestinal bleed must receive optimization of his bleed- ing risk (PPI, endoscopies, interruption of aspirin and other insults).55,56 Data suggest that anticoagulation may be safely resumed beyond the first 7 days of the bleed, with a dramatic reduction of thromboembolic risk and a similar bleeding safety compared to anticoagulation re-initiation later than 30–90 days.

C. Anticoagulation in acute TIA or stroke, and after intracranial bleed

Patients with AF who develop TIA should be started on effective anticoagulation as soon as possible. Conversely, anticoagulation is postponed 3–6 days in small cerebral infarction, and 12 days in large cerebral infarction, given the risk of hemorrhagic transformation (ESC guidelines).31 It is reasonable to rule out hemorrhagic transformation by head CT before starting anticoagulation.

After an intracranial bleed, anticoagulation may be reconsidered, at 4–8 weeks, in patients with very high thromboembolic risk whose bleeding risk factor has been treated (e.g., HTN that is now controlled, berry aneurysm that is coiled or clipped).31 Patients with deep cerebral bleeds are considered, as well as subdural hematoma after surgical evacuation. Multiple meta-analyses have shown the benefit and safety of resuming anticoagulation. Anticoagulation is generally avoided after lobar/cortical bleed (amyloid angiopathy).

D. Therapy in patients with AF and CAD- Question of triple combination of aspirin, clopidogrel and oral anticoagulation

The major bleeding risk is ~1–2% per year with aspirin, and ~3% per year with warfarin. The addition of aspirin to warfarin increases the yearly bleeding risk to ~ 4% per year.57,58 On the other hand, the triple combination of aspirin, clopidogrel, and an anticoagulant has a 4× higher major bleeding risk than aspirin + anticoagulant (12% vs. 3–4% yearly bleeding risk).58 In patients with AF or LV thrombus who undergo stent placement, the question is whether the risk of this triple combination is warranted. According to WOEST (using warfarin), PIONEER-AF (rivaroxaban), RE-DUAL PCI (dabigatran), and AUGUSTUS (apixaban) trials, patients with AF undergoing PCI with DES may be treated with the dual combination of clopidogrel and one anticoagulant, with no aspirin therapy beyond the first 1–7 days after PCI (ACS in 50–61% of patients).5963 In fact, the dual combination clopidogrel-anticoagulant was much safer than the triple combination aspirin-clopidogrel-anticoagulant, used for 1–6 months, with similar protection from MI and stent thrombosis, significant bleeding reduction, and mortality reduction in one of the trials (WOEST). The combined inhibition of the thrombin pathway with anticoagulation and the ADP pathway with clopidogrel may lessen the importance of cyclooxygenase inhibition with aspirin. As a result, initial double therapy is currently recommended and preferred over initial triple therapy in all patients (clopidogrel+ warfarin or preferably NOAC: apixaban 5 mg bid, rivaroxaban 15 mg qd, or dabigatran 150 mg bid) (ESC and North American consensus).31,64 Triple therapy, for 1 month only, may be considered in patients who have a combined high ischemic risk/low bleeding risk, as suggested by AUGUSTUS substudy.65

Beyond one year of PCI or MI, single therapy with an anticoagulant is recommended (no aspirin nor clopidogrel) and appears to reduce mortality, bleeding and cardiovascular events compared to anticoagulant+single antiplatelet (AFIRE trial with rivaroxaban, and registry data).66,67 In fact, anticoagulation, per se, reduces not only embolic events but coronary events as well; this was well shown in old warfarin trials. Compared to placebo, warfarin monotherapy reduced mortality and recurrent MI after an acute MI;68 compared to aspirin, warfarin monotherapy further reduced recurrent MI.69,70

E. Role of clopidogrel

The ACTIVE W study has shown that in patients with AF and moderate to high thromboembolic risk (CHADS2 score 2 ± 1), warfarin monotherapy is clearly superior to the combination of aspirin and clopidogrel for the reduction of cardiovascular events (yearly rate 3.9% vs. 5.6%, p <0.001), stroke (1.4% vs. 2.4%, p <0.001), and even MI (trend), with a similar major bleeding risk (~2% per year).71

Table 10.6 Major bleeding risk associated with HAS-BLED risk score in patients receiving warfarin.

HAS-BLED score Major bleeding per year
0 1%
1 1%
2 1.9%
3 3.75%
4 8.7%
5 12.5%
Data from Euro Heart Survey.

The ACTIVE A study has shown that the combination of aspirin and clopidogrel is superior to aspirin monotherapy for stroke prevention in AF (yearly rate 2.4% vs. 3.3%, p <0.001), at the cost of more major bleeding (2% per year vs. 1.3% per year, p <0.001).72 Thus, the combination of aspirin and clopidogrel appears to be an option superior to aspirin but inferior to warfarin. Since this combination has the same bleeding risk as warfarin, it has no definite role in AF therapy, particularly with the availability of NOACs that facilitate chronic therapy.

VIII. Special situation: atrial fibrillation and heart failure. Optimal heart rate in heart failure

A. General management

In a patient presenting with decompensated HF, AF may be:

  1. secondary to HF
  2. the cause of the cardiomyopathy and HF (tachycardia- or AF-mediated cardiomyopathy)
  3. the major trigger of HF decompensation in a patient with a previously stable cardiomyopathy

It should be assumed that either (b) or (c) is the case, but at the stage of decompensated HF acute DCCV may not be helpful.

In compensated HF, AF contributes to ~30–40% of cardiac output. Those patients have a large A wave with E/A reversal on echo, confirming the crucial role of atrial contraction. In fast AF, the loss of atrial systole and the reduction of diastolic filling time reduce cardiac output, which increases LA pressure and decompensates HF. However, once HF is decompensated, even if the patient converts back to sinus rhythm, the contribution of atrial systole to cardiac output will be marginal. In fact, decompensated patients have a very small A wave on echo, as the high LV pressure does not allow any filling during atrial contraction (Figure 10.1). At this point:

  • Tachycardia of 100–110 bpm may be helpful, as it increases cardiac output and LV emptying by increasing the number of cardiac cycles per minute. Cardiac contractility also increases up to a heart rate of 100–110 (Bowditch phenomenon).
  • Tachycardia >120 bpm is however counterproductive and reduces the contractility of the energy-depleted myocardium, cardiac output and VO2 (particularly HFrEF).73,74 AF needs to be acutely rate controlled to <110–120 bpm (ESC <110 bpm).
  • Tachycardia >130 bpm with severe hemodynamic compromise (shock, severe pulmonary edema) often needs acute DCCV, particularly in systolic HF, to improve LV energetics and contractility.

In addition, treatment of HF with diuresis and vasodilators slows down AF and possibly converts it (situation (a) above). Once HF is stabilized and diuresed, the goal becomes to slow down AF to a rate <100 bpm at rest and better yet, cardiovert it;19 at the compensated stage, the atrial kick increases cardiac output and reduces HF symptoms, and sinus rhythm reverses AF-mediated cardiomyopathy.

Schematic illustration of LV diastolic filling pattern in compensated HF, decompensated HF, decompensated HF secondary to AF, and effects of DCCV.

Figure 10.1 LV diastolic filling pattern in compensated HF, decompensated HF, decompensated HF secondary to AF, and effects of DCCV.

B. Rate control in HF (Table 10.7)

Table 10.7 Rate control of AF with or without HF.

No HF β-blocker or CCB or combination
Decompensated HF with low EF No β-blocker and no CCB Diuresis/HF therapy

IV digoxin or amiodarone (class I indication)

Once compensated, start β-blocker then uptitrate it
Decompensated HF with normal EF May use β-blocker or CCB
Compensated HF with low EF β-blocker (may be uptitrated faster than usually done in HF)

C. Effect of AF on EF and value of AF ablation in HF

AF, by itself, even when rate controlled, reduces stroke volume and EF (=AF-induced cardiomyopathy). That is why trials of AF ablation in HFrEF have consistently shown an EF rise of 10–30% after ablation, mainly in persistent AF, even when AF rate is controlled (eg, CAMERA-MRI trial and Hsu trial, where patients with controlled ventricular rate had EF improvement of 18 +/-13% after ablation).7678 Even in the PABA-CHF trial that compared AF ablation to AV nodal ablation with biventricular pacing, EF was 8% higher in sinus rhythm than in AF.79

This is partly explained by the Frank-Starling relationship. Less ventricular filling (preload) per cycle results in less contractility (preload-related contractility), lower stroke volume and therefore, lower EF. Patients must be at a compensated stage, preload dependent, able to increase their filling with atrial systole to benefit from the Frank-Starling relationship.

As importantly, irregularity of ventricular rate, by itself, reduces cardiac output (CO).80,81 As such, one study of AF patients undergoing AV nodal ablation showed that irregular V pacing mimicking AF is associated with a 16% lower CO and a higher PCWP than regular V pacing at the same rate.81 The very short RR interval reduces stroke volume more than the long RR interval makes up for it.80,82 Rate irregularity creates harmful calcium mishandling and overload in the myocardium, as well as catecholamine activation (during pauses).

In relation to all this, CASTLE-AF trial randomized patient with systolic HF and symptomatic AF (paroxysmal or persistent [70%]), who are relatively young (median age 65) and not morbidly obese (median BMI 29), to AF ablation vs medical therapy (mainly rate control, with rhythm control in 30%).78 In comparison to medical therapy, AF ablation dramatically reduced mortality by 45% (13% vs 25%) and HF hospitalizations, despite the moderate-to-severe LA enlargement (median LA diameter 4.9 cm), and improved EF by 7.3% in paroxysmal AF and 10% in persistent AF (vs 0.2% in medical therapy). While AF recurrence rate was 50% in the ablation arm, AF burden was dramatically reduced by ablation, and, in fact, it was not necessary to eliminate AF but to reduce its burden; AF burden best correlated with outcomes (AF burden was reduced from a mean of 51% at baseline to ~25% with AF ablation; AF burden <6% was associated with 3.3 times less death and HF hospitalizations). At baseline, 45% of the patients had already tried and failed or not tolerated amiodarone; ~30% of the medical therapy arm re-attempted it after randomization. Similarly, AATAC trial showed a mortality reduction with AF ablation vs amiodarone in HFrEF.83 AF ablation is given a class IIa indication in HFrEF, and a class I indication when AF is believed to be the cause of low EF (ESC).

While AF ablation is preferred in HF patients with AF, it seems that AV nodal ablation with CRT pacing, even if QRS<110 ms, is still superior to medical therapy for permanent AF and results in less HF hospitalization and physical limitation/dyspnea (APAF-CRT trial).84 In the HF setting, medical therapy for symptomatic AF is least effective on HF outcomes and functional limitation (harmful irregularity +/-inadequate rate control).

IX. Special situation: atrial fibrillation with borderline blood pressure or non-AF-related hypotension

In critical illness, a fast rate of up to 120 bpm may be appropriate and tolerated. In patients with borderline BP, or full-blown shock not caused by AF (e.g., septic shock with AF at 120–150 bpm), IV amiodarone may be used for rate control <120 bpm (ACC and ESC). Amiodarone may precipitate hypotension but only during fast boluses (<30 min). Amiodarone has limited rhythm controlling effect in the first 24–48 hours. Digoxin IV may also be used but its vagal effect is ineffective in high catecholamine states.

β-Blockers may be cautiously used in the absence of a pre-shock state, wherein the patient is dependent on the adrenergic tone and wherein β-blockers drop BP precipitously (e.g., severe hypovolemia, sepsis, bleeding). Esmolol IV, being quickly reversible, is the preferred β-blocker in this instance.

AF with clear-cut shock and a rate >150 bpm (or 130 bpm in systolic HF) is often contributive to the shock and DC cardioverted emergently, unless a clear cause of hypotension is identified, such as massive gastrointestinal bleed. IV procainamide may be attempted for acute cardioversion, even in HF, to avert the need for DCCV’s sedation (except in extremis).

Nov 27, 2022 | Posted by in CARDIOLOGY | Comments Off on Atrial Fibrillation

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