#CardsJC: EAST-AFNET4 Trial

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CardioNerds Journal Club is a monthly forum for Cardionerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the EAST-AFNET4 Trial.

Table of contents:

October 1st, 2020

Early Rhythm-Control Therapy in Patients with Atrial Fibrillation

The EAST-AFNET4 Trial

P. Kirchhof, A.J. Camm, A. Goette, A. Brandes, L. Eckardt, A. Elvan, T. Fetsch, I.C. van Gelder, D. Haase, L.M. Haegeli, F. Hamann, H. Heidbüchel, G. Hindricks, J. Kautzner, K.-H. Kuck, L. Mont, G.A. Ng, J. Rekosz, N. Schoen, U. Schotten, A. Suling, J. Taggeselle, S. Themistoclakis, E. Vettorazzi, P. Vardas, K. Wegscheider, S. Willems, H.J.G.M. Crijns, and G. Breithardt.

N Engl J Med 2020; 383:1305-1316

Relevant Literature

  • Atrial fibrillation (AF) is the most common cardiac arrhythmia.
  • Previous trials have not shown superiority of rhythm control with antiarrhythmic drugs over rate control in patients with established AF.1
  • Rhythm control therapy may be more effective when delivered early.2,3

Relevant Guidelines4,5

The primary indication for rhythm control is to reduce AF-related symptoms and improve quality of life. The routine use of a rhythm-control strategy is not universally recommended; an initial rate-control strategy is reasonable for many patients.

Rate control strategies:

  • Control of ventricular rate using a beta blocker or nondihydropyridine calcium channel antagonist is recommended for patients with paroxysmal, persistent, or permanent AF (Class I).
  • A goal resting heart rate of < 80 bpm is reasonable for symptomatic AF (Class IIa). A lenient rate-control strategy (<110 bpm) can be considered in asymptomatic patients with preserved systolic LV function (Class IIb).
  • Oral amiodarone may be useful for ventricular rate control when other measures are unsuccessful or contraindicated (Class IIb).
  • AV nodal ablation with permanent ventricular pacing can be considered, if pharmacological therapy is inadequate and rhythm control is not achievable (Class IIa).

Rhythm control strategies:

  • Patients with AF have increased risk of stroke and adverse cardiovascular outcomes, even with current guideline-based therapy.6
  • Previous trials have not shown survival benefit or reduction in major cardiovascular events with a rhythm control strategy, as the adverse effects of rhythm control therapy appear to limit the benefits gained from maintaining sinus rhythm.1 However, there is evidence that prior trial participants with early AF had better outcomes of rhythm control therapy than those with longstanding AF.7
  • There remains equipoise about whether an early rhythm control strategy using modern rhythm control therapies is beneficial in reducing the risk of CV complications for patients with AF.

Objective

The Early Treatment of AF for Stroke Prevention Trial (EAST-AFNET 4) was designed to test whether a strategy of early rhythm-control therapy that includes AF ablation would be associated with better outcomes in patients with early AF than contemporary, evidence-based usual care.

EAST-AFNET4 Trial

  • International (France, Denmark, Netherlands, Italy, Switzerland, Belgium, Czech Republic, Spain, Great Britain, Poland, Germany), prospective, randomized, investigator-initiated, parallel-group, open, blinded-outcome-assessment.

Intervention

  • Patients with AF diagnosed within 1 year were randomized 1:1 to either receive early rhythm control (n = 1,395) or usual care (n = 1,394).
    • Early rhythm control: antiarrhythmic drugs or AF ablation, as well as cardioversion of persistent AF, after randomization.
    • Usual care: initially treated with rate-control therapy without rhythm control. Limited rhythm control to the management of AF-related symptoms.

Enrollment criteria 

Outcomes

Statistical Analysis

  • Trial designed as an event-driven trial

Notable Baseline Characteristics

  • Patients were enrolled a median of 36 days (interquartile range, 6 to 112) after the first diagnosis of AF.
  • Demographic and clinical characteristics were generally well balanced.
    • Digitalis glycosides and beta-blockers slightly more common in usual care group
    • Statins slightly more common in rhythm control group

Primary Outcome

  • Trial stopped for efficacy at the third interim analysis after a median follow-up of 5.1 years per patient.
  • First-primary-outcome event (composite of cardiovascular death, stroke, or hospitalization for heart failure or acute coronary syndrome) occurred in:
    •  249 patients assigned to early rhythm control (3.9 per 100 person-years)
    •  316 patients assigned to usual care (5.0 per 100 person-years)
    • HR 0.79 (96% CI 0.66-0.94); P=0.0058
  • Second primary outcome event (number of nights spent in the hospital) not significantly different between both groups.

Secondary Outcomes

  • No significant difference between rhythm control and usual care with regards to:
    • Symptoms
    • LV function
    • Cognitive function
  • Sinus rhythm was found more often in patients who had been randomly assigned to receive early rhythm control (84.9% at 1 year, 82.1% at 2 years) than in patients assigned to receive usual care (65.5% at 1 year, 60.5% at 2 years).
  • At 2 years, 88.0% assigned to early rhythm control and 90.9% assigned to usual care were still taking oral anticoagulants.

Adverse events

  • Did not differ significantly between the groups; serious adverse events related to rhythm-control therapy occurred in 4.9% of the patients assigned to early rhythm control and 1.4% of the patients assigned to usual care.
  • Mortality was similar in the two treatment groups, and stroke occurred less frequently among patients assigned to early rhythm control than among those assigned to usual care.
  • Early-rhythm control therapy in patients with early AF and CV conditions was associated with a lower risk of death from cardiovascular causes, stroke, or hospitalization for heart failure or acute coronary syndrome than usual care over a follow-up time of more than 5 years, without affecting the number of nights spent in the hospital.
  • Most patients (>70%) were asymptomatic at 1 and 2 years in both treatment groups, and the magnitude of change in LV function did not differ between the groups at 2 years.
  • The incidence of the overall safety outcome events was similar in the two groups.

Limitations & Considerations

  • Compared two treatment strategies that necessitated an open trial design.
  • Only enrolled patients with early AF, and thus the results may not be generalizable to patients in whom early rhythm-control therapy that includes AF ablation is initiated later.
  • All enrolled patients deemed eligible for either rate-control or rhythm-control therapy, which probably excluded the most symptomatic patients.
  • Did not collect detailed information on recurrent AF in both groups, so data on percentages of patients with sinus rhythm are not comparable to data on recurrent AF from other rhythm-control trials.
  1. 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):1825-33.
  2. Nattel S, Guasch E, Savelieva I, et al. Early management of atrial fibrillation to prevent cardiovascular complications. Eur Heart J. 2014;35(22):1448-56.
  3. Kirschoff P, Bax, J, Blomstrom-Lunquist C, et al. Early and comprehensive management of atrial fibrillation: executive summary of the proceedings from the 2nd AFNET-EHRA consensus conference ‘research perspectives in AF’. Eur Heart J. 2009;30(24):2969-2777.
  4. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64(21):e1-e76.
  5. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2021;42(5):373-498.
  6. Marijon E, Le Heuzey JL, Connolly S, et al. Causes of death and influencing factors in patients with atrial fibrillation: a competing-risk analysis from the randomized evaluation of long-term anticoagulation study. Circulation. 2013;128(20):2192-2201.
  7. Damluji A, Al-Damluji M, Marzouka, et al. New-onset versus prior history of atrial fibrillation: Outcomes from the AFFIRM trial. 2015;170(1):156-163.

SUMMARY BY: 

Dr. Teodora Donisan, @TDonisan, PGY2 Internal Medicine Resident, Beaumont, Royal Oak, MI
Dr. Patrick Zakka@PatrickZakka, PGY4 Internal Medicine Chief Resident, Emory University, Atlanta, GA.

VISUAL ABSTRACT BY: 

Dr. Madiha Khan, @madhattans, internal medicine resident at Houston Methodist Hospital, Houston, TX

JOURNAL CLUB PROMO GRAPHIC BY: 

Dr. Luis Calderon, @LMCalderonMD, Hospitalist at MedStar Washington Hospital Center, Washington DC

HOUSE TAUSSIG CHIEF FELLOWS

Dr. Rick Ferraro, @RichardAFerraro, internal medicine resident at the Johns Hopkins Hospital, Baltimore MD

Dr. Eunice Dugan, @EuniceDuganMD, internal medicine resident at the Johns Hopkins Hospital, Baltimore MD

AMBASSADOR

Dr. Kelly Arps @kellyarps, Cardiology Fellow at Duke University, Durham, NC.

ASSOCIATE SCIENCE PROGRAM DIRECTOR

Dr. Carine Hamo, @CarineHamo, cardiology fellow at the Johns Hopkins Hospital, Baltimore, MD

The published archive features curated twitter highlights from the journal club event.

Gernal Atrial Fibrillation

Hugh Calkins @HughCalkinsMD

Almost all ablation studies show a higher stroke risk in patients who present in continuous AF. Stroke risk has fallen greatly with uninterrupted NOACS but the increased risk remains.

In the old days we were taught that stroke risk was unrelated to AF burden. It is now clear this was false. What we need now is a new CHADSVasc that incorporates AF burden into stroke risk.

JK Han MD @netta_doc

Totally agree Rachita – AF and obesity go hand-in-hand as has been so elegantly elucidated by @PrashSanders group. Just look at how these CDC maps overlap.

Amit Goyal @AmitGoyalMD

@HafizaKMD thank you for teaching us the ABCs of AF!

EASTAF-NET4 vs AFFRIM

Hugh Calkins @HughCalkinsMD

The Affirm study was in a very different population and it was flawed with many rhythm control patients in AF and vice versa. This study was in an early AF population with much better compliance to the treatment strategy.

Kamala Tamirisa MD @KTamirisaMD

AFFIRM – Not early AF patients, Anti-arrhythmic meds comfort levels were lower…

And, Anticoagulants were stopped in AFFIRM

Andrea Russo @AndreaRussoEP

Hard to compare results of EAST-AFNET4 to older trials and this current study looks at EARLY rhythm control (diagnosed within 1 year before enrollment; median time to dx 36 days). Compared to older studies, findings suggest we should treat AF early with rhythm control!

Subgroup analysis of AFFIRM showed those w/AF dx <6 months had no difference in outcome (survival, CV Hosp, stroke) in rate vs. rhythm control – suggests more than timing, e.g., improved rhythm control strategies (i.e., incl ablation & GDMT for drugs) & more use of OAC.

Pranav Chandrashekar @pranavc91

Agreed. And on a similar note I feel we quote affirm and race so often on inpatient rounds when it really wasn’t an inpatient study. The population was ambulatory in these trials and a very different inclusion criteria than trainees are used to seeing.

Amin Al-Ahmad, MD @aalahmadmd

One issue I have with of the AFFIRM study is when it is assumed that patients are asymptomatic without giving a trial of sinus rhythm.  It is worth remembering that many people accommodate for a AF by decreasing activity.

Jonathan Chrispin @JonChrispinMD

I agree. I have found many patients with persistent AF did not realize how symptomatic they were until sinus rhythm was restored

I am not surprised. Most AF symptoms are due to inadequate rate control. On the same note, tachycardia-induced cardiomyopathies will also improve with good rate control. But as I tell the fellows, the best form of rate control is rhythm control in appropriate patients.

CABANA tried to answer this question. While the ITT analysis showed no difference, those that did get an AF ablation had less AF, better QOL, and lower risk of the composite outcome of mortality and CV hospitalization

Rachita Navara, MD @DrRachitaEP

Re: assessing Sx in AF, I appreciated this clinic pearl from @DoctorPhillEP: patients may deny any AF Sx. If their DCCV success was short-lived, imp to ask if patients noticed feeling better in that period! Affects our aggressiveness to pursue NSR esp if persistent AF

Shoutout for the near-50% representation of female patients in a pivotal arrhythmia trial

Andrea Russo @AndreaRussoEP

JK Han MD @netta_doc

Great point, Rachita! And I thought we did great with CABANA at 37%!

Absolutely! Best seen in patients with CIEDs post-AF ablation – so many instances where interrogation graphs show that when AF stops, patient activity increases.

Justice Oranefo @OranefoJustice

Rhythm control was maintained in 82% of patients in the early rhythm control group as opposed to 62% in the AFFIRM trial. This likely played a role in better outcomes in EAST-AFNET 4

Nino Isakadze  @NinoIsakadze
Patrick Zakka, MD @PatrickZakka

STOP AF trial and EARLY AF trial showing deceased recurrence of AF in ablation vs drug therapy group might suggest that if ablation was used as a rhythm control method alone benefits might have been even greater.. thoughts?

Patrick Zakka, MD @PatrickZakka: Love this Nino, also wonder how the CABANA trial ties in to this. More NSR with ablation vs AADs. Also better QOL. I wonder how we can do a trial that avoids cross over since having patients on antiarrhythmic group may eventually need ablation.

Karan Desai MD @karanpdesai

Major takeaway for me in this trial is to note early ablation was infrequent (8% early, 20% had undergone by 2 years). ERC does not necessarily equal early ablation. ERC = all risk factor modification +/- AAD at its foundation

Medication concerns

Amit Goyal @AmitGoyalMD

Dronederone was unavailable for AFFIRM trial.  Use of safer AADs may have been one reason for (+) results of EAST AFNET 4.

Patrick Zakka, MD @PatrickZakka

Dronedarone is interesting. More in EAST-AFNET4 since unavailable in 2002. Less side effects, rare hepatotoxicity reported. Also wonder about its chronic use in persistent AF patients (ANDROMEDA, PALLAS trials).

Hugh Calkins @HughCalkinsMD

Dronederone clearly should not be used as a rate control agent in patients with permanent AF. The beauty of this drug is that all trials started it as an outpatient. I have never seen hepatotoxicity with it.

G. Stuart Mendenhall, MD @GSMedicine

Well, yes and no… Let’s not ignore dronedarone two FDA ‘black box’ warnings in specific population, but yes for healthy paroxysmal patient extremely safe. https://t.co/rKFb4DqQVq

Timing of Intervention

Dinu V. Balanescu, M.D. @dinubalanescu

Is there such a thing as too early in AF rhythm control? How do AFFIRM and EAST-AFNET4 differ?

Jonathan Chrispin @JonChrispinMD

It is never too early! The key is maintaining sinus rhythm. AF is a progressive disease and you want to intervene before adverse atrial remodeling occurs.

Mikhael El-Chami @melchami99

Pursuing rhythm control at early stages typically results in more success in maintaining sinus rhythm. The presence of sinus rhythm was a predictor of improved outcomes in AFFIRM.

Hugh Calkins @HughCalkinsMD

In my mind standard teaching is behind the times. There are enormous benefits to rhythm control. And if you do not pursue rhythm control early and a patient is in continuous AF you will miss the window. 

Context is important. Clearly major surgery and hyperthyroidism can trigger AF. For these patients less is more

Keith Andrew Chan @keithachanmd

Wow! Current dictum is probably summarized as “Catch early, convert early”

James Tooley, MD @JamesETooley

Pts were enrolled <12 mo after an AF diagnosis. We don’t know much about how the diagnosis was made… considering ~30% of patients were asymptomatic at enrollment should we actively look for asymptomatic patients with AF to treat with *even earlier* rhythm control?

Kamala Tamirisa MD @KTamirisaMD

@JamesETooley You opened the pandora’s box 😀 – a million dollar Q – Pondering about the pitfalls of “aggressive screening”….costs, anxiety, inappropriate RFA for short runs of PAT

Daniel Cantillon MD @djcantillonmd

In our center’s 2016 study, shorter time to ablation = better outcomes for persistent AF.  Q1 was <1 yr from Dx.

Screening

James Tooley, MD @JamesETooley

The early rhythm control group was randomized to single lead ECG monitoring twice weekly and w/ symptoms. Do you think this monitoring strategy was important to their benefit? Are you using these digital health devices in this way in your patients?

Jason Andrade @DrJasonAndrade

Depends what you’re trying to achieve. If it’s to prove no af recurrences, then you need continuous monitoring. If it’s to improve patient quality of life then symptom monitoring is reasonable, recognizing you will miss 50% of recurrences with this protocol.

Moeen Saleem, MD @MoeenSaleem

Agree with @DrJasonAndrade. QOL and symptoms may not require as frequent monitoring. AF recurrence and the more complex decision re continuing OAC would need more continuous monitoring data.

Amit Goyal @AmitGoyalMD

BMI is reported, but OSA is not!  Obesity and sleep apnea are important risk factors and likely impact AF outcomes.

Daniel Cantillon MD @djcantillonmd

This is a really important point @AmitGoyalMD as I’d argue true “contemporary” rhythm control should address all modifiable risk factors (OSA, BMI, Alcohol, etc.) in addition to consideration for early catheter ablation

Jason Andrade  @DrJasonAndrade

Hugh Calkins @HughCalkinsMD

Great point, Same with weight loss. We proceed with ablation but at the same time encourage weight reduction. If you delay ablation for either sleep apnea treatment or weight loss you will have a remodeled atrium!

Amit Goyal @AmitGoyalMD

Inclusion of the elderly was important since in practice we’re often less aggressive with rhythm control in older patients.

Jonathan Chrispin @JonChrispinMD

This is a point not to be overlooked. Older patients with co-morbidities were included and the study highlights the safety of AAD therapy in this population

Hugh Calkins @HughCalkinsMD

Ablation studies have shown similar outcomes in your and very elderly patients (over 80) that are well selected. Rhythm control should be offered to all patients with AF symptoms regardless of age. I think we all can recognize patients where it is best to call it quits.

The best predictor of ability to maintain sinus rhythm is AF type and then AF duration. Any patient with paroxysmal AF is a good candidate for rhythm control if symptoms. It is the long-standing persistent its with a LA > 5.5 cm that are a much tougher journey to sinus

It is amazing how much LA size alone can tell you about the success of catheter ablation. If you do a preprocedure CT the LA is either a plum or a grapefruit. The grapefruit patients are too far gone and AF almost always returns.

Kamala Tamirisa MD @KTamirisaMD

Age is not a barrier for quality of life – unless the ablation risks outweigh benefits. #CardsJC They might still be running everyday w zero comorbidities

Jonathan Chrispin @JonChrispinMD

Certainly the longer you are in continuous AF, the lower the chance of maintaining sinus rhythm with AAD or ablation. Other factors are important such as LA size, fibrosis on CMR. Managing expectations is key

Digital Health

James Tooley, MD @JamesETooley

Should health insurance cover digital health devices to monitor for AF burden in our patients? Or to monitor for recurrence as they were used for the early rhythm control group in EAST-AFNET?

JK Han MD @netta_doc

Would love to see this happen. More and more data coming out that early recurrence after #AFib ablation in blanking period predicts true recurrence later. But need to balance that with not causing anxiety in our patients. Need to tailor type of device to the patient…

James Tooley, MD @JamesETooley

Apple Watch anxiety is real…

Jonathan Chrispin @JonChrispinMD

I use mobile ECG devices frequently for symptom/rhythm correlation. Particularly for episodes that are too infrequent to be detected with standard Holter/Event monitors.

JK Han MD @netta_doc

Use of #digitalhealth tools has been indispensable in our AF patients, esp those who are symptomatic – these tools can provide great on-the-spot help with correlating symptoms to arrhythmias.

Nino Isakadze @NinoIsakadze

So far,  “rhythm check” with digital health technologies in my patients are used only with symptoms but as we learn more about AF burden screening for recurrent AF without symptoms will likely be beneficial

#CardsJC: EAST-AFNET4 Trial