Linking To The 2024 ESC Guidelines On Atrial Fibrillation “7. [R] Reduce symptoms by rate and rhythm control”

Today, I review, link to, and excerpt from The European Society Of Cardiology 2024 Guidelines On Atrial Fibrillation, “7. [R] Reduce symptoms by rate and rhythm control“.

All that follows is from the above resource.

7. [R] Reduce symptoms by rate and rhythm control

Most patients diagnosed with AF will need therapies and/or interventions to control heart rate, revert to sinus rhythm, or maintain sinus rhythm to limit symptoms or improve outcomes. While the concept of choosing between rate and rhythm control is often discussed, in reality most patients require a combination approach which should be consciously re-evaluated during follow-up. Within a patient-centred and shared-management approach, rhythm control should be a consideration in all suitable AF patients, with explicit discussion of benefits and risks.

7.1. Management of heart rate in patients with AF

Limiting tachycardia is an integral part of AF management and is often sufficient to improve AF-related symptoms. Rate control is indicated as initial therapy in the acute setting, in combination with rhythm control therapies, or as the sole treatment strategy to control heart rate and reduce symptoms. Limited evidence exists to inform the best type and intensity of rate control treatment.⁴⁵⁷ The approach to heart rate control presented in Figure 7 can be used for all types of AF, including paroxysmal, persistent, and permanent AF.

Figure 7: [R] Pathway for patients with permanent AF.

AF, atrial fibrillation; AF-CARE, Atrial fibrillation—[C] Comorbidity and risk factor management, [A] Avoid stroke and thromboembolism, [R] Reduce symptoms by rate and rhythm control, [E] Evaluation and dynamic reassessment; b.p.m., beats per minute; CRT, cardiac resynchronization therapy; HF, heart failure; LVEF, left ventricular ejection fraction. Permanent AF is a shared decision made between the patient and physician that no further attempts at restoration of sinus rhythm are planned. ^aNote that the combination of beta-blockers with diltiazem or verapamil should only be used under specialist advice, and monitored with an ambulatory ECG to check for bradycardia.

Recommendation Table 14: Recommendations for heart rate control in patients with AF (see also Evidence Table 14)

7.1.1. Indications and target heart rate

The optimal heart rate target in AF patients depends on the setting, symptom burden, presence of heart failure, and whether rate control is combined with a rhythm control strategy. In the RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation) RCT of patients with permanent AF, lenient rate control (target heart rate <110 [beats per minute] b.p.m.) was non-inferior to a strict approach (<80 b.p.m. at rest; <110 b.p.m. during exercise; Holter for safety) for a composite of clinical events, NYHA class, or hospitalization.^186,459 Similar results were found in a post-hoc combined analysis from the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) and the RACE (Rate Control versus Electrical cardioversion) studies.⁴⁷⁴ Therefore, lenient rate control is an acceptable initial approach, unless there are ongoing symptoms or suspicion of tachycardia-induced cardiomyopathy, where stricter targets may be indicated.

7.1.2. Heart rate control in the acute setting

In acute settings, physicians should always evaluate and manage underlying causes for the initiation of AF prior to, or in parallel to, instituting acute rate and/or rhythm control. These include treating sepsis, addressing fluid overload, or managing cardiogenic shock. The choice of drug (Table 12) will depend on the patient’s characteristics, presence of heart failure and LVEF, and haemodynamic profile (Figure 7). In general for acute rate control, beta-blockers (for all LVEF) and diltiazem/verapamil (for LVEF >40%) are preferred over digoxin because of their more rapid onset of action and dose-dependent effects.^462,475,476 More selective beta-1 receptor blockers have a better efficacy and safety profile than unselective beta-blockers.⁴⁷⁷ Combination therapy with digoxin may be required in acute settings (combination of beta-blockers with diltiazem/verapamil should be avoided except in closely monitored situations).^177,478 In selected patients who are haemodynamically unstable or with severely impaired LVEF, intravenous amiodarone, landiolol, or digoxin can be used.^472,473,479

7.1.3. Long-term heart rate control

Pharmacological rate control can be achieved with beta-blockers, diltiazem, verapamil, digoxin, or combination therapy (Table 12) (see Supplementary data online, Additional Evidence Table S15).⁴⁸⁰

Table 12: Drugs for rate control in AF

Agenta	Intravenous administration	Usual range for oral maintenance dose	Contraindicated
Beta-blockersb
Metoprolol tartrate	2.5–5 mg bolus over 2 mins; up to 15 mg maximal cumulative dose	25–100 mg twice daily	In case of asthma, non-selective beta-blockers should be avoided. Contraindicated in acute HF and history of severe bronchospasm.
Metoprolol XL (succinate)	N/A	50–200 mg once daily
Bisoprolol	N/A	1.25–20 mg once daily
Atenololc	N/A	25–100 mg once daily
Esmolol	500 µg/kg i.v. bolus over 1 min; followed by 50–300 µg/kg/min	N/A
Landiolol	Optional loading dose of 100 µg/kg i.v. bolus over 1 min, followed by 10–40 µg/kg/min. In critically ill patients (cardiac dysfunction, septic shock) start with 1–10 µg/kg/min and titrate according to response	N/A
Nebivolol	N/A	2.5–10 mg once daily
Carvedilol	N/A	3.125–50 mg twice daily
Non-dihydropyridine calcium channel antagonists
Verapamil	2.5–10 mg i.v. bolus over 5 min	40 mg twice daily to 480 mg (extended release) once daily	Contraindicated if LVEF ≤40%. Adapt doses in hepatic and renal impairment.
Diltiazem	0.25 mg/kg i.v. bolus over 5 min, then 5–15 mg/h	60 mg three times daily to 360 mg (extended release) once daily
Digitalis glycosides
Digoxin	0.5 mg i.v. bolus (0.75–1.5 mg over 24 h in divided doses)	0.0625–0.25 mg once daily	High plasma levels associated with adverse events. Check renal function before starting digoxin and adapt dose in CKD patients.
Digitoxin	0.4–0.6 mg	0.05–0.1 mg once daily
Other
Amiodaroned	300 mg i.v. diluted in 250 mL 5% dextrose over 30–60 min (preferably via central venous cannula), followed by 900–1200 mg i.v. over 24 h diluted in 500–1000 mL via a central venous cannula	200 mg once daily after loading Loading: 200 mg three times daily for 4 weeks, then 200 mg daily or less as appropriate (reduce other rate control drugs according to heart rate)	Contraindicated in iodine sensitivity. Serious potential adverse effects (including pulmonary, ophthalmic, hepatic, and thyroid). Consider numerous drug interactions.

AF, atrial fibrillation; CKD, chronic kidney disease; HF, heart failure; i.v., intravenous; min, minutes; N/A, not available or not widely available. Maximum doses have been defined based on the summary of product characteristic of each drug.

^aAll rate control drugs are contraindicated in Wolff–Parkinson–White syndrome; also intravenous amiodarone.

^bOther beta-blockers are available but not recommended as specific rate control therapy in AF and therefore not mentioned here (e.g. propranolol and labetalol).

^cNo data on atenolol; should not be used in heart failure with reduced ejection fraction or in pregnancy.

^dLoading regimen may vary; i.v. dosage should be considered when calculating total load.

© ESC 2024

The choice of rate control drugs depends on symptoms, comorbidities, and the potential for side effects and interactions. Combination therapy of different rate-controlling drugs should be considered only when needed to achieve the target heart rate, and careful follow-up to avoid bradycardia is advised. Combining beta-blockers with verapamil or diltiazem should only be performed in secondary care with regular monitoring of heart rate by 24 h ECG to check for bradycardia.⁴⁵⁹ Some antiarrhythmic drugs (AADs) also have rate-limiting properties (e.g. amiodarone, sotalol), but they should generally be used only for rhythm control. Dronedarone should not be instituted for rate control since it increases rates of heart failure, stroke, and cardiovascular death in permanent AF.⁴⁸¹

Beta-blockers, specifically beta-1 selective adrenoreceptor antagonists*, are often first-line rate-controlling agents largely based on their acute effect on heart rate and the beneficial effects demonstrated in patients with chronic HFrEF. However, the prognostic benefit of beta-blockers seen in HFrEF patients with sinus rhythm may not be present in patients with AF.^133,482

*Selective Beta-1 Blockers, StatPearls, William D. Tucker; Parvathy Sankar; Pramod Theetha Kariyanna. Last Update: January 30, 2023.

“The cardio-selective beta-1-blockers include atenolol, betaxolol, bisoprolol, esmolol, acebutolol, metoprolol, and nebivolol.”

Verapamil and diltiazem are non-dihydropyridine calcium channel blockers. They provide rate control⁴⁶¹ and have a different adverse effect profile, making verapamil or diltiazem useful for those experiencing side effects from beta-blockers.⁴⁸³ In a 60 patient crossover RCT, verapamil and diltiazem did not lead to the same reduction in exercise capacity as seen with beta-blockers, and had a beneficial impact on BNP.⁴⁸⁰

Digoxin and digitoxin are cardiac glycosides that inhibit the sodium–potassium adenosine triphosphatase and augment parasympathetic tone. In RCTs, there is no association between the use of digoxin and any increase in all-cause mortality.^185,484 Lower doses of digoxin may be associated with better prognosis.¹⁸⁵ Serum digoxin concentrations can be monitored to avoid toxicity,⁴⁸⁵ especially in patients at higher risk due to older age, renal dysfunction, or use of interacting medications. In RATE-AF (RAte control Therapy Evaluation in permanent Atrial Fibrillation), a trial in patients with symptomatic permanent AF, there was no difference between low-dose digoxin and bisoprolol for patient-reported quality of life outcomes at 6 months. However, those randomized to digoxin demonstrated fewer adverse effects, a greater improvement in mEHRA and NYHA scores, and a reduction in BNP.⁴⁸ Two ongoing RCTs are addressing digoxin and digitoxin use in patients with HFrEF with and without AF (EudraCT-2013-005326-38, NCT03783429).⁴⁸⁶

Due to its broad extracardiac adverse effect profile, amiodarone is reserved as a last option when heart rate cannot be controlled even with maximal tolerated combination therapy, or in patients who do not qualify for atrioventricular node ablation and pacing. Many of the adverse effects from amiodarone have a direct relationship with cumulative dose, restricting the long-term value of amiodarone for rate control.⁴⁸⁷

7.1.4. Atrioventricular node ablation and pacemaker implantation

Ablation of the atrioventricular node and pacemaker implantation (‘ablate and pace’) can lower and regularize heart rate in patients with AF (see Supplementary data online, Additional Evidence Table S16). The procedure has a low complication rate and a low long-term mortality risk.^468,488 The pacemaker should be implanted a few weeks before the atrioventricular node ablation, with the initial pacing rate after ablation set at 70–90 b.p.m.^489,490 This strategy does not worsen LV function,⁴⁹¹ and may even improve LVEF in selected patients.^492,493 The evidence base has typically included older patients. For younger patients, ablate and pace should only be considered if heart rate remains uncontrolled despite consideration of other pharmacological and non-pharmacological treatment options. The choice of pacing therapy (right ventricular or biventricular pacing) depends on patient characteristics, presence of heart failure, and LVEF.^187,494

In severely symptomatic patients with permanent AF and at

least one hospitalization for heart failure, atrioventricular node ablation combined with CRT should be considered. In the APAF-CRT (Ablate and Pace for Atrial Fibrillation-cardiac resynchronization therapy) trial in a population with narrow QRS complexes, atrioventricular node ablation combined with CRT was superior to rate control drugs for the primary outcomes (all-cause mortality, and death or hospitalization for heart failure), and secondary outcomes (symptom burden and physical limitation).^470,471 Conduction system pacing may become a potentially useful alternate pacing mode when implementing a pace and ablate strategy, once safety and efficacy have been confirmed in larger RCTs.^495,496 In CRT recipients, the presence (or occurrence) of AF is one of the main reasons for suboptimal biventricular pacing.¹⁸⁷ Improvement of biventricular pacing is indicated and can be reached by intensification of rate control drug regimens, atrioventricular node ablation, or rhythm control, depending on patient and AF characteristics.¹⁸⁷

7.2. Rhythm control strategies in patients with AF

7.2.1. General principles and anticoagulation

Rhythm control refers to therapies dedicated to restoring and maintaining sinus rhythm. These treatments include cardioversion, AADs, percutaneous catheter ablation, endoscopic and hybrid ablation, and open surgical approaches (see Supplementary data online, Additional Evidence Table S17). Rhythm control is never a strategy on its own; instead, it should always be part of the AF-CARE approach.

In patients with acute or worsening haemodynamic instability thought to be caused by AF, rapid electrical cardioversion is recommended. For other patients, a wait-and-see approach should be considered as an alternative to immediate cardioversion (Figure 12). The Rate Control versus Electrical Cardioversion Trial 7–Acute Cardioversion versus Wait and See (RACE 7 ACWAS) trial in patients with recent-onset symptomatic AF without haemodynamic compromise showed a wait-and-see approach for spontaneous conversion until 48 h after the onset of AF symptoms was non-inferior as compared with immediate cardioversion at 4 weeks follow-up.¹⁰

Figure 12: Approaches for cardioversion in patients with AF.

AF, atrial fibrillation; CHA₂DS₂-VA, congestive heart failure, hypertension, age ≥75 years (2 points), diabetes mellitus, prior stroke/transient ischaemic attack/arterial thromboembolism (2 points), vascular disease, age 65–74 years; h, hour; LMWH, low molecular weight heparin; DOAC, direct oral anticoagulant; OAC, oral anticoagulant; TOE, transoesophageal echocardiography; UFH, unfractionated heparin; VKA, vitamin K antagonist. Flowchart for decision-making on cardioversion of AF depending on clinical presentation, AF onset, oral anticoagulation intake, and risk factors for stroke. ^aSee Section 6.

Since the publication of landmark trials more than 20 years ago, the main reason to consider longer-term rhythm control therapy has been the reduction in symptoms from AF.^497–500 Older studies have shown that the institution of a rhythm control strategy using AADs does not reduce mortality and morbidity when compared with a rate control-only strategy,^497–500 and may increase hospitalization.⁴⁵⁷ In contrast, multiple studies have shown that rhythm control strategies have a positive effect on quality of life once sinus rhythm is maintained.^501,502 Therefore, in the case of uncertainty of the presence of symptoms associated with AF, an attempt to restore sinus rhythm is a rational first step. In patients with symptoms, patient factors that favour an attempt at rhythm control should be considered, including suspected tachycardiomyopathy, a brief AF history, non-dilated left atrium, or patient preference.

Rhythm control strategies have significantly evolved due to an increasing experience in the safe use of antiarrhythmic drugs,¹⁷ consistent use of OAC, improvements in ablation technology,^503–509 and identification and management of risk factors and comorbidities.^39,510,511 In the ATHENA trial (A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg twice daily for the Prevention of Cardiovascular Hospitalization or Death from Any Cause in Patients with Atrial Fibrillation/Atrial Flutter), dronedarone significantly reduced the risk of hospitalization due to cardiovascular events or death as compared with placebo in patients with paroxysmal or persistent AF.⁵¹² The CASTLE-AF trial (Catheter Ablation versus Standard Conventional Treatment in Patients With Left Ventricle Dysfunction and AF) demonstrated that a rhythm control strategy with catheter ablation can improve mortality and morbidity in selected patients with HFrEF and an implanted cardiac device.⁴ In end-stage HFrEF, the CASTLE-HTx trial (Catheter Ablation for Atrial Fibrillation in Patients With End-Stage Heart Failure and Eligibility for Heart Transplantation) found, in a single centre, that catheter ablation combined with guideline-directed medical therapy significantly reduced the composite of death from any cause, implantation of left ventricular assist device, or urgent heart transplantation compared with medical treatment.⁵¹³ At the same time, however, the CABANA trial (Catheter Ablation versus Anti-arrhythmic Drug Therapy for Atrial Fibrillation) could not demonstrate a significant difference in mortality and morbidity between catheter ablation and standard rhythm and/or rate control drugs in symptomatic AF patients older than 64 years, or younger than 65 years with risk factors for stroke.³ EAST-AFNET 4 (Early treatment of Atrial fibrillation for Stroke prevention Trial) reported that implementation of a rhythm control strategy within 1 year compared with usual care significantly reduced the risk of cardiovascular death, stroke, or hospitalization for heart failure or acute coronary syndrome in patients older than 75 years or with cardiovascular conditions.¹⁷ Of note, rhythm control was predominantly pursued with antiarrhythmic drugs (80% of patients in the intervention arm). Usual care consisted of rate control therapy; only when uncontrolled AF-related symptoms occurred was rhythm control considered. Patients in the EAST-AFNET 4 trial all had cardiovascular risk factors but were at an early stage of AF, with more than 50% being in sinus rhythm and 30% being asymptomatic at the start of the study.

Based on all of these studies, this task force concludes that implementation of a rhythm control strategy can be safely instituted and confers amelioration of AF-related symptoms. Beyond control of symptoms, sinus rhythm maintenance should also be pursued to reduce morbidity and mortality in selected groups of patients.^{4,17,502,513,514}

Any rhythm control procedure has an inherent risk of thromboembolism. Patients undergoing cardioversion require at least 3 weeks of therapeutic anticoagulation (adherence to DOACs or INR >2 if VKA) prior to the electrical or pharmacological procedure. In acute settings or when early cardioversion is needed, transoesophageal echocardiography (TOE) can be performed to exclude cardiac thrombus prior to cardioversion. These approaches have been tested in multiple RCTs.^319–321 In the case of thrombus detection, therapeutic anticoagulation should be instituted for a minimum of 4 weeks followed by repeat TOE to ensure thrombus resolution. When the definite duration of AF is less than 48 hours, cardioversion has typically been considered without the need for pre-procedure OAC or TOE for thrombus exclusion. However, the ‘definite’ onset of AF is often not known, and observational data suggest that stroke/thromboembolism risk is lowest within a much shorter time period.^515–519 This task force reached consensus that safety should come first. Cardioversion is not recommended if AF duration is longer than 24 hours, unless the patient has already received at least 3 weeks of therapeutic anticoagulation or a TOE is performed to exclude intracardiac thrombus. Most patients should continue OAC for at least 4 weeks post-cardioversion. Only for those without thromboembolic risk factors and sinus rhythm restoration within 24 h of AF onset is post-cardioversion OAC optional. In the presence of any thromboembolic risk factors, long-term OAC should be instituted irrespective of the rhythm outcome.

Recommendation Table 15: Recommendations for general concepts in rhythm control (see also Evidence Table 15)

7.2.2. Electrical cardioversion

start here.