Rate Versus Rhythm Control for Atrial Fibrillation

Abstract

Atrial fibrillation (AF) is an arrhythmia characterized by disorganized atrial activity with an associated unevenly irregular ventricular response on an electrocardiogram. It is the most common sustained arrhythmia, with a lifetime risk of 25% in patients older than 40 years old. The incidence of AF increases with age and is associated with an increased risk for heart failure, stroke, adverse cardiac events, and dementia. The 2 main aims of AF treatment include anticoagulation for thromboembolism prophylaxis as well as rate vs rhythm control. The focus of this article will be on the treatment strategies in managing AF. Rate control refers to the use of atrioventricular nodal blocking medications, including beta blockers and calcium channel blockers, to maintain a goal heart rate. Rhythm control, on the other hand, refers to a treatment strategy focused on the use of antiarrhythmic drugs (AAD), cardioversion, and ablation to restore and to maintain a patient in sinus rhythm. Currently, the ideal treatment strategy remains greatly debated. Thus, we hope to compare the risks and benefits of rate to rhythm control to highlight how patients with AF are managed here at Kaiser Permanente Northern California.

Point: We Should Continue With Rate Control as It Is the Current Standard of Practice!

What Are the Studies That Made Rate Control a Desirable Treatment Option for Our Patients With Atrial Fibrillation?

The landmark AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) trial¹ was the first, and one of the largest, clinical studies to compare the use of rate control vs rhythm control for atrial fibrillation (AF) patients. This was a large-scale, observed clinical trial that included 4060 participants with nonvalvular AF who had a high likelihood of stroke or death. The trial demonstrated that there was no survival advantage between the rate control and rhythm control strategies. More importantly, however, it demonstrated a higher mortality associated with the rhythm control strategy, particularly in those > 65 years old and those without a history of heart failure (HF).² The optimal heart rate was addressed with the RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation) trial,² which showed no difference in terms of mortality, hospitalizations for HF, arrhythmia related symptoms, and thromboembolic complications when controlling the rate below 80 vs 110 beats per minute.^2,3 As a result, it has been common practice for Kaiser Permanente Northern California patients with AF to be rate controlled with a goal heartrate < 110 beats per minute (Table).

Table:

Rate vs rhythm control

Aspect	Rate Control	Rhythm Control
Primary goal	Controlling ventricular heart rate	Restoring and maintaining sinus rhythm
Options	Beta blockers, calcium channel blocks, and digoxin	Flecainide, sotalol, amiodarone, dronedarone, cardioversion, and ablation
Ideal patients	Multiple comorbidities, large atrial enlargement, and longstanding AF	Young age, symptomatic AF, persistent HF despite rate control, and difficulty maintaining rate control
Chance of thromboembolism	Based off CHADVASC2a scoring; will require Direct Oral Anticoagulation therapy	Despite achieving sinus rhythm, patients will be kept on lifelong anticoagulants
Pros	Easy to initiate and often the treatment strategy for new AF in the inpatient setting	Early rhythm control has been linked with lower all-cause mortality, cardiovascular mortality, stroke, and HF hospitalizations
Cons	May continue to be asymptomatic and the long-term effects of rate control are unknown	Requires monitoring when initiating AADs and limited ablation sites for Kaiser Permanente Northern California

^aA scoring system for atrial fibrillation patients to see which patients would benefit from a blood thinning medication given the risks rewards ratio.

AADs, antiarrhythmic drugs; AF, atrial fibrillation; DOAC, direct oral anticoagulants; HF, heart failure.

Who Might Benefit the Most From Rate Control?

The Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial⁴ sought to determine whether rhythm control was beneficial in patients with HF. This 2008 multicentered, prospective, randomized trial found that among the 1376 patients with AF who also have HF with reduced ejection fraction, rhythm control did not reduce cardiovascular mortality statistically significant when compared with rate control.⁵ As such, rhythm control should be considered for patients who experience symptoms from AF or worsening HF despite adequate rate control. Other patient populations who may benefit from early rhythm control include younger patients, those with drug-refractory AF, and patients with ischemic heart disease whose condition may be exacerbated by rapid heart rates or irregular rhythms.^1,6

What Are Some Drawbacks of Rate Control?

Despite the support for rate control, we must also consider the limitations of this treatment strategy. One limitation to consider in the AFFIRM trial is the change in practices since the study was conducted (1995–2001). For instance, it is now the standard of care for patients who receive rhythm control agents to remain on anticoagulation regardless of effectiveness of strategy. This is in stark contrast to the AFFIRM trial when patients were able to discontinue anticoagulation after being in sinus rhythm for 4 weeks.⁷ In contrast, the rate control patients remained on their antithrombotic treatment regimen. Although the AFFIRM trial found similar rates of ischemic strokes in both the rhythm and the rate control groups, it is possible that longer term anticoagulation therapy could have led to lower stroke risk in the rhythm control group. Additionally, an important rhythm control treatment option not tested in the AFFIRM trial was ablation strategy, which will be discussed later in the article. With the rhythm control group completely reliant on antiarrhythmic drugs (AADs), primarily amiodarone and sotalol, side effects and toxicities associated with these medications may have also contributed to adverse outcomes. Finally, AF is a chronic condition that can affect younger patients without comorbidities, but the AFFIRM trial’s patient population was selective for older individuals with a relatively short median follow-up period of only 3.5 years.¹ Therefore, while rate control may be the preferred treatment in older individuals, it may not be prudent to generalize the findings to all patients.⁸

Counterpoint: We Should Consider Rhythm Control as Practices Have Changed Since the AFFIRM Trial

What Are the Studies That Made Rhythm Control a Desirable Treatment Option for Patients With AF?

Importantly, the AFFIRM trial’s inclusion criteria comprised patients > 65 years old with AF diagnosis that was likely to be chronic and recurrent. The question remained as to whether early rhythm control might alter the natural history of AF and therefore the long-term outcome. This was the primary focus of the multicenter EAST-AFNET4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial),⁹ which enrolled patients to either rhythm control via AADs or ablation therapy, while the other treatment arm received typical rate control, with both groups treated within 12 months of their AF diagnosis. The EAST-AFNET4 trial was stopped for efficacy after a median of 5 years with the early rhythm control group having a lower chance of cardiovascular mortality, stroke, HF hospitalization, acute coronary syndrome–related hospitalizations, and stroke.¹⁰ Overall, this study supports the idea of the use of early rhythm control strategies for AF over rate control strategies.

Radiofrequency ablation therapy, which is a minimally invasive therapy targeting and scarring the area around the pulmonary veins to prevent further propagation and triggering of AF, has demonstrated good efficacy in select patient groups to maintain sinus rhythm and does not pose the same likelihood of long-term side effects as AADs.^11,12 As such, this is another treatment option that has shown promise as a rhythm control agent, especially for those who responded well to cardioversion in the past. This was supported by the 2018 CASTLE-AF clinical trial,¹³ which highlighted the effectiveness of ablation therapy with a 16.1% absolute reduction in death or hospitalization for HF when compared to medical therapy (rate or rhythm control).¹⁴ This difference was driven by an 11.6% absolute reduction in death and a 15.2% absolute reduction in hospitalization for HF.¹⁴ This study adds to the emerging evidence that catheter ablation is associated with improved rhythm control in patients with AF and symptomatic systolic HF as well as improved cardiovascular outcomes in this population. The results suggest that catheter ablation may be a reasonable first-line treatment for patients with AF who also have HF.

Who Might Benefit From Rhythm Control?

One possible reason for improved outcomes with early rhythm control may be related to preventing negative atrial remodeling effects related to arrhythmias. Han et al performed a systematic review of early rhythm control vs rate control in AF on studies published from January 1, 2020, to April 15, 2022.¹⁵ From this 2023 systematic review, which focused primarily on 7 clinical trials, including the EAST-AFNET4 trial and the AFFIRM trial, early rhythm control was linked to lower all-cause mortality, cardiovascular mortality, stroke, and HF hospitalizations.¹⁶ This supports the idea that maintaining sinus rhythm early in natural history could prevent complications on the heart from prolonged AF.

What Are Some Drawbacks of Rhythm Control?

Despite these benefits of early rhythm control, as of January 2021, no guidelines have been published that reflect the results of the EAST-AFNET4 trial. Rhythm control is generally only recommended to improve symptoms and quality of life in symptomatic patients with AF. One major consideration to keep in mind is how difficult it was to keep patients in sinus rhythm. For instance, Han et al discusses that in the RACE II trial, only 39% were able to be kept in sinus rhythm through the entirety of the study, including with the use of AADs.¹⁷ Similar difficulties in maintaining sinus rhythm were also seen with the Strategies of Treatment of Atrial Fibrillation (STAF) trial, How to Treat Chronic Atrial Fibrillation (HOT CAFÉ) Trial, and Pharmacologic Intervention in Atrial Fibrillation (PIAF) trials^18–20. The EAST-AFNET4 trial also raised this question, as it remains up to debate whether patients from the rhythm control group truly benefited from receiving the AAD or from ablation therapy, as nearly 20% of patients in the rhythm control group underwent ablation.¹⁰ However, the overall difficulty of maintaining long-term rhythm control, particularly in the AAD group in these studies, should prompt more careful examination of risk–benefit ratio.

Some of the many barriers in starting rhythm control are the well-established side effects and risks from the various available options. Class 1C antiarrhythmics, which bind to open or inactivated sodium channels in cardiac cells, slowing down the rate of depolarization and reducing the conduction velocity of electrical impulses through cardiac tissues, are common AADs used for rhythm control. Although effective, they carry known side effects, including inducing new or worsening existing arrhythmias, especially in those with known structural heart disease.^15,21,22 Amiodarone, another common rhythm control agent, can induce systemic side effects, including pulmonary toxicity, thyroid dysfunction, and liver toxicity, and carries various drug-to-drug interactions. Amiodarone has also been associated with skin reactions, including photosensitivity as well as bluish-gray discoloration. Additionally, patients on amiodarone are encouraged to have regular eye examinations to assess for corneal deposits, optic neuropathy, or visual disturbances. Dronedarone, an antiarrhythmic medication that is structurally related to amiodarone but thought to carry a better safety profile, also carries inherent risks such as QT prolongation, liver toxicity, interstitial lung disease, and drug-to-drug interaction.²³ Ablation for AF carries the chance of procedural complications, including cardiac perforation, stroke, myocardial infarction, esophageal injury, phrenic nerve injury, and pulmonary vein stenosis.²⁴

Another barrier to consider when initiating antiarrhythmic therapy is how resource-intensive the process can be to mitigate some of the associated risks. Patients with AF who are to be started on class 1C AADs such as flecainide or propafenone should not have evidence of structural heart disease, as supported by the Cardiac Arrhythmia Suppression Trial.^12,21,25 Preinitiation workup would include an echocardiogram and stress test. Some groups also recommend routine postinitiation treadmill stress testing to ensure that the QRS interval does not widen with faster heart rates. Complicating matters, there are no national standard guidelines on pre- or postinitiation stress testing and how often follow-up electrocardiogram (ECG), echocardiography, or stress testing is needed. Patients started on class 3 agents such as sotalol and dofetilide need to have close electrocardiographic follow-up to ensure that QT corrected for heart rate is not excessively prolonged.^10,20,23 For dofetilide, this involves a mandatory hospitalization during initiation. Sotalol is often initiated in the outpatient setting, with a follow-up ECG after the fifth dose, although some centers recommend inpatient initiation as with dofetilide.^3,22,26 Patients on class 3 agents need to have regular ECG monitoring and avoidance of other QT corrected for heart rate prolonging agents to avoid life-threatening arrhythmias. Patients on amiodarone need to have regular screenings for thyroid, liver, and lung function. Ablation therapy is a resource-intensive option limited to electrophysiology-capable centers. Regionally, for Kaiser Permanente Northern California, this is limited to Santa Clara and Sacramento. AF ablation might be used for first-line therapy only in select groups with high likelihood of success and patient benefit. Success rates for AF ablation decrease with larger atrial volumes, longer AF duration, and older age.^11,14,27,28

Conclusion

Rate vs rhythm control for the optimal treatment of AF has been a long-debated topic. Both have their merits, flaws, and clinical trials that support their use. Decisions need to be made on a case-by-case basis after informed and shared decision making with the patient.

Patient factors that would benefit most from rhythm control include young age, significant AF symptoms, persistent HF despite rate control, and difficulty with adequate rate control despite high doses of medications or inability to tolerate them. In contrast, rate control would be best utilized in patients with multiple comorbidities, severe left atrial enlargement, and longstanding persistent AF that would make the risks of AADs and ablation therapy outweigh potential benefits.