Rate versus Rhythm Control in Patients with Atrial Fibrillation: Time to Change the Paradigm?

Authors: Christopher Cheung MD (biography, no disclosures), Kenneth Gin MD (biography and disclosures), and Jason G. Andrade MD. Disclosures: Research for Bayer, Ad board Bayer, BI, Pfizer. Mitigating potential bias: Only published trial data is presented. Recommendations are consistent with current practice patterns.

What I did before

Patients with atrial fibrillation (AF) or flutter can be managed with a strategy of either acceptance of the abnormal rhythm with control of ventricular rate (“rate-control”) or attempts to maintain the patient in normal sinus rhythm (“rhythm-control”). Current guidelines preferentially recommend patients with persistent AF be managed with rate-control, particularly if patients are less symptomatic from their AF.¹ In contrast, rhythm-control may be preferred in patients with intermittent (paroxysmal) or highly symptomatic AF, or with a history of cardiomyopathy.¹

The reason for these recommendations stems from large randomized controlled trials performed at the turn of the century. The largest study to compare rate- versus rhythm-control was the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, which randomized 4060 patients in a 1:1 ratio to rhythm-control with anti-arrhythmic medications and/or cardioversion, or rate-control targeting a resting heart rate (HR) ≤ 80 bpm and 6-minute-walk HR ≤ 110 bpm.² In AFFIRM, the average age of patients was 70 years old (39% female) with a minority of patients being enrolled after their first episode of AF.² Most patients randomized to rhythm-control received amiodarone or sotalol. The AFFIRM trial reported no significant difference in the overall mortality associated with a rate- versus rhythm-control strategy.² Other trials, including Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation (RACE), Strategies of Treatment of Atrial Fibrillation (STAF), and Atrial Fibrillation and Congestive Heart Failure (AF-CHF), found similar results albeit with smaller study populations.^3-5

What changed my practice

The EAST-AFNET 4 study was a large multicenter randomized trial comparing early rhythm-control versus usual care in patients with newly diagnosed AF, defined as AF diagnosed within 12 months of enrollment.⁶ The study included 2789 patients (age 18 years or older) who were randomized in a 1:1 ratio to rhythm-control with anti-arrhythmic drugs and/or catheter ablation versus usual care with rate-control. Patients randomized to the rhythm-control strategy were required to transmit a single-lead ECG twice per week and while symptomatic. The first primary outcome was a composite of death from cardiovascular causes, ischemic or hemorrhagic stroke, or hospitalization due to heart failure or acute coronary syndrome. The secondary primary outcome was the number of nights spent in hospital. The primary safety outcome was a composite of all-cause mortality, stroke, or serious adverse event secondary to rhythm-control therapy.

The average age of patients enrolled in EAST-AFNET 4 was 70 years, with 46% female and an average CHA₂DS₂-VASc score of 3.4.⁶ Patients had a combination of first episode AF (38%), paroxysmal AF (36%), and persistent AF (26%). Approximately 30% of patients were asymptomatic, and 55% of patients were in sinus rhythm at baseline. Among patients randomized to the rhythm control strategy, 95% of patients were receiving rhythm control at baseline, most commonly using flecainide (36%) and amiodarone (20%). Approximately 8% of patients underwent catheter ablation of AF at baseline, with 19% undergoing ablation at 2-years. In the usual care group, 96% of patients were managed with rate control at baseline and 85% remained on rate control at 2-years.

The trial was stopped early for efficacy at the 75% interim analysis, after a median follow-up of 5.1 years. The first primary outcome (composite of cardiovascular death, stroke, and hospitalization) occurred in 249 patients in the rhythm-control group, compared to 316 patients in the usual care group, (hazard ratio [HR] of 0.79; 95% confidence interval [CI] 0.66-0.94).⁶ There was also a significant reduction in death from cardiovascular causes (HR 0.72, 95% CI 0.52-0.98), and stroke (HR 0.65, 95% CI 0.44-0.97). There was no significant difference in the secondary primary outcome of nights in hospital, or the primary safety outcome of composite stroke, death, and adverse events. There was a numerical increase in serious adverse events due to rhythm control therapy in the rhythm-control group, compared to usual care (4.9% vs. 1.4% over the 5-year follow-up period). This corresponded to a number-needed-to-harm of 28 patients over 5-years to cause a serious adverse event (anti-arrhythmic drug toxicity, drug-induced bradycardia, and/or hospitalization for AF). At 2-year follow-up, there was no significant difference in quality of life measures between groups, with almost 75% of patients being asymptomatic.

The EAST-AFNET 4 trial demonstrated a significant reduction in the composite of cardiovascular death, stroke, and hospitalization with rhythm control therapy compared to usual care. Importantly, all components of the composite outcome favoured rhythm control, with significant reductions in the individual endpoints of cardiovascular death and stroke. Furthermore, all subgroups appeared to benefit equally from a rhythm control strategy (including older age, presence of heart failure, asymptomatic AF, persistent AF). While it is possible that the closer monitoring of the rhythm control group resulted in improved outcomes, anticoagulation rates remained equivalent across both groups (90%) at 2-year follow-up.⁶ The findings translate to a number-needed-to-treat of 18 patients over 5-years with rhythm control to prevent one cardiovascular death, stroke, or hospitalization.⁶

What I do now

The EAST-AFNET 4 trial provides supportive evidence that a rhythm control strategy is safe and potentially reduces cardiovascular death, stroke, and hospitalization compared to usual care, in patients with a recent diagnosis of AF (within the past 12 months).⁶ These findings mark a departure from previous large clinical trials approximately two decades prior, including the AFFIRM, RACE, STAF, and AF-CHF trials cited earlier.^2-5 Notable differences in these studies include the enrollment of patients earlier in their AF course, as well as the use of contemporary anti-arrhythmic medications. Patients in the AFFIRM trial randomized to rhythm control predominantly received amiodarone (63%) or sotalol (41%), which have been associated with increased mortality.² In addition, catheter ablation of AF is now a treatment option for patients with symptomatic AF seeking rhythm control – in EAST-AFNET 4, 19% of patients received catheter ablation of AF at the 2-year follow-up.⁶ Lastly, patients in the AFFIRM study randomized to rhythm control who were noted to be in sinus rhythm were provided the option for discontinuing anticoagulation, a treatment paradigm that has been subsequently disproven owing to increased risk of stroke on follow-up. In contrast, patients in both arms of the EAST-AFNET 4 trial received anticoagulation as per guidelines, regardless of underlying rhythm.

Current guidelines recommend that a rhythm control strategy should be pursued in patients with paroxysmal AF, those with highly symptomatic AF, younger patients, those with relatively fewer medical comorbidities, and those with a history of congestive heart failure exacerbated by AF or AF-related cardiomyopathy.^7-9 Patients with persistent AF, less symptomatic and/or older patients, and those with prior anti-arrhythmic failure are best managed with a rate control strategy.^7-9 The EAST-AFNET 4 trial is a practice changing trial, and strongly supports the role of early rhythm control in patients with newly-diagnosed AF. Importantly, almost one-third of patients in EAST-AFNET 4 trial were asymptomatic, and had a mean age of 70 years, representing a population traditionally managed by rate control. While the findings of EAST-AFNET 4 may change our understanding of the rate vs. rhythm control management, the other fundamental principles of AF management remain unchanged. Patients with an elevated stroke risk (CHADS₂ score ≥1 or age ≥65 years) should receive anticoagulation irrespective of the rate vs. rhythm management strategy, and the integrated approach to managing modifiable cardiovascular risk factors remains of paramount importance.

Tips for the General Practitioner

Management of AF continues to change with new literature and our evolving understanding of AF. Practical tips for the general practitioner caring for a patient with AF can be distilled to the following:

• Baseline evaluation for new AF diagnoses, including identifying AF triggers, treating reversible precipitants, and managing cardiovascular risk factors. Patients should undergo a complete history and cardiopulmonary examination, with routine investigations including laboratory investigations (i.e. blood count, coagulation profile, renal and liver function, thyroid function), 12-lead electrocardiogram, and echocardiogram.
• Evaluation of thromboembolic risk and initiate anticoagulation where indicated, according to the Canadian Cardiovascular Society (CCS) algorithm (“CHADS-65”).⁹ This occurs irrespective of rate or rhythm control. Patients who are 65 years or older, or have CHADS₂ risk factors (history of congestive heart failure, hypertension, diabetes, age, or previous stroke or TIA) meet guideline indications for long-term anticoagulation for stroke prevention.
• Unstable patients, defined as AF causing hypotension, acute coronary syndrome, or acute heart failure decompensation, should be referred for urgent assessment in an acute care environment. Hemodynamically stable but highly symptomatic patients, require urgent specialist assessment to determine the ideal long-term treatment strategy. This can usually be accomplished as an outpatient.
• Rate control therapy (beta-blocker, verapamil, diltiazem, or digoxin) should be initiated for patients with persistent AF and rapid ventricular response (resting heart rate ≥100 bpm), pending determination of the long-term AF management strategy, (e.g. rate- vs. rhythm-control).
• Choosing between a rate versus rhythm control strategy requires balancing AF pathophysiology, symptom burden, and patient preference. Patients with AF requiring arrhythmia education, additional care (i.e. highly symptomatic, heart failure, cardiac devices), or advanced therapies (i.e. failed anti-arrhythmic drugs, considering catheter ablation) can be referred to a specialist, or the local Atrial Fibrillation clinic.
  1. Less symptomatic older patients with persistent AF should be preferentially treated with a long-term rate control strategy.
  2. Rhythm control is preferred in highly symptomatic patients, those with paroxysmal AF and/or new-onset AF, in younger patients with relatively few medical comorbidities, and those with a history of congestive heart failure exacerbated by AF or AF-related cardiomyopathy. Options for rhythm control are further discussed in the CCS AF guidelines.⁹
  3. Patients with insidious onset AF or those with vague symptoms may benefit from a trial of rhythm control (i.e. cardioversion) with assessment to see if symptoms improve with sinus rhythm.

References:

1. Verma A, Cairns JA, Mitchell LB, et al. 2014 focused update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation. Can J Cardiol. 2014;30(10):1114-1130. doi:10.1016/j.cjca.2014.08.001 (View with CPSBC or UBC)
2. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347(23):1825-1833. doi:10.1056/NEJMoa021328 (Request with CPSBC or view UBC)
3. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med. 2002;347(23):1834-1840. doi:10.1056/NEJMoa021375 (Request with CPSBC or view UBC)
4. Carlsson J, Miketic S, Windeler J, et al. Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol. 2003;41(10):1690-1696. doi:10.1016/s0735-1097(03)00332-2 (View)
5. Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med. 2008;358(25):2667-2677. doi:10.1056/NEJMoa0708789 (Request with CPSBC or view UBC)
6. Kirchhof P, Camm AJ, Goette A, et al. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. N Engl J Med. 2020;383:1305-1316. doi:10.1056/NEJMoa2019422 (Request with CPSBC or view UBC)
7. Macle L, Cairns J, Leblanc K, et al. 2016 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation. Can J Cardiol. 2016;32(10):1170-1185. doi:10.1016/j.cjca.2016.07.591 (View with CPSBC or UBC)
8. Andrade JG, Verma A, Mitchell LB, et al. 2018 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation. Can J Cardiol. 2018;34(11):1371-1392. doi:10.1016/j.cjca.2018.08.026 (View with CPSBC or UBC)
9. Andrade JG, Aguilar M, Atzema C, et al. The 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society Comprehensive Guidelines for the Management of Atrial Fibrillation. Can J Cardiol. 2020 Oct 22:S0828-282X(20)30991-0. (View)

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Rate versus Rhythm Control in Patients with Atrial Fibrillation: Time to Change the Paradigm?

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