Systematic, early rhythm control strategy for atrial fibrillation in patients with or without symptoms: the EAST-AFNET 4 trial

Stephan Willems, Katrin Borof, Axel Brandes, Günter Breithardt, A John Camm, Harry J G M Crijns, Lars Eckardt, Nele Gessler, Andreas Goette, Laurent M Haegeli, Hein Heidbuchel, Josef Kautzner, G André Ng, Renate B Schnabel, Anna Suling, Lukasz Szumowski, Sakis Themistoclakis, Panos Vardas, Isabelle C van Gelder, Karl Wegscheider, Paulus Kirchhof, Stephan Willems, Katrin Borof, Axel Brandes, Günter Breithardt, A John Camm, Harry J G M Crijns, Lars Eckardt, Nele Gessler, Andreas Goette, Laurent M Haegeli, Hein Heidbuchel, Josef Kautzner, G André Ng, Renate B Schnabel, Anna Suling, Lukasz Szumowski, Sakis Themistoclakis, Panos Vardas, Isabelle C van Gelder, Karl Wegscheider, Paulus Kirchhof

Abstract

Aims: Clinical practice guidelines restrict rhythm control therapy to patients with symptomatic atrial fibrillation (AF). The EAST-AFNET 4 trial demonstrated that early, systematic rhythm control improves clinical outcomes compared to symptom-directed rhythm control.

Methods and results: This prespecified EAST-AFNET 4 analysis compared the effect of early rhythm control therapy in asymptomatic patients (EHRA score I) to symptomatic patients. Primary outcome was a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome, analyzed in a time-to-event analysis. At baseline, 801/2633 (30.4%) patients were asymptomatic [mean age 71.3 years, 37.5% women, mean CHA2DS2-VASc score 3.4, 169/801 (21.1%) heart failure]. Asymptomatic patients randomized to early rhythm control (395/801) received similar rhythm control therapies compared to symptomatic patients [e.g. AF ablation at 24 months: 75/395 (19.0%) in asymptomatic; 176/910 (19.3%) symptomatic patients, P = 0.672]. Anticoagulation and treatment of concomitant cardiovascular conditions was not different between symptomatic and asymptomatic patients. The primary outcome occurred in 79/395 asymptomatic patients randomized to early rhythm control and in 97/406 patients randomized to usual care (hazard ratio 0.76, 95% confidence interval [0.6; 1.03]), almost identical to symptomatic patients. At 24 months follow-up, change in symptom status was not different between randomized groups (P = 0.19).

Conclusion: The clinical benefit of early, systematic rhythm control was not different between asymptomatic and symptomatic patients in EAST-AFNET 4. These results call for a shared decision discussing the benefits of rhythm control therapy in all patients with recently diagnosed AF and concomitant cardiovascular conditions (EAST-AFNET 4; ISRCTN04708680; NCT01288352; EudraCT2010-021258-20).

Keywords: Ablation; Antiarrhythmic drugs; Atrial fibrillation; Clinical trial; Rhythm control; Symptoms.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Figures

Graphical Abstract
Graphical Abstract
Figure 1
Figure 1
Consort flow chart of the patients included in this analysis showing screening, randomization, treatment, and follow-up. Of all patients included into the EAST-AFNET 4 trial, 21 of the 2810 patients did not meet the inclusion criteria of early atrial fibrillation (diagnosed ≤1 year before enrolment) and cardiovascular conditions. After exclusion of 156 patients with missing baseline symptom status, 2633 patients were included into the analysis with randomization to early rhythm control (n = 1305) or usual care (n = 1328). Most of the patients assigned to early rhythm-control were initially treated with antiarrhythmic drugs, regardless of symptom status. After 2 years of follow-up, 242 of the 395 asymptomatic patients (59.3%) and 601 of the 910 symptomatic patients (64.8%) who had been randomly assigned to early rhythm control therapy were still receiving active rhythm-control therapy [atrial fibrillation ablation in 75/395 (19.0%) asymptomatic patients and in 176/910 (19.3%) symptomatic patients; P = 0.672] randomized to early rhythm control. This corresponds to ca 25% of patients randomized to early rhythm control and still in follow-up at 24 months.
Figure 2
Figure 2
Aalen–Johansen cumulative-incidence curves for the first primary outcome: (A) for patients with asymptomatic atrial fibrillation at baseline and (B) for patients with symptomatic atrial fibrillation at baseline. The first primary outcome was a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome. The effect of early rhythm control on this outcome was almost identical in symptomatic and asymptomatic patients.
Figure 3
Figure 3
Change in atrial fibrillation symptoms between discharge from baseline and 24 months follow-up. There were no differences in symptom status at 24 months between randomized groups, irrespective of the presence of baseline symptoms (P = 0.1161). Symptoms improved without inter-group difference, illustrating the good adherence to protocol in patients randomized to usual care, which included symptom-directed rhythm control therapy to improve atrial fibrillation-related symptoms.

References

    1. Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomstrom-Lundqvist C, Boriani G, Castella M, Dan GA, Dilaveris PE, Fauchier L, Filippatos G, Kalman JM, La Meir M, Lane DA, Lebeau JP, Lettino M, Lip GYH, Pinto FJ, Thomas GN, Valgimigli M, Van Gelder IC, Van Putte BP, Watkins CL; ESCSD Group. 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;42:373–498.
    1. Xiong Q, Proietti M, Senoo K, Lip GY. Asymptomatic versus symptomatic atrial fibrillation: a systematic review of age/gender differences and cardiovascular outcomes. Int J Cardiol 2015;191:172–177.
    1. Schnabel RB, Pecen L, Ojeda FM, Lucerna M, Rzayeva N, Blankenberg S, Darius H, Kotecha D, Caterina R, Kirchhof P. Gender differences in clinical presentation and 1-year outcomes in atrial fibrillation. Heart 2017;103:1024–1030.
    1. Boriani G, Laroche C, Diemberger I, Fantecchi E, Popescu MI, Rasmussen LH, Sinagra G, Petrescu L, Tavazzi L, Maggioni AP, Lip GY. Asymptomatic atrial fibrillation: clinical correlates, management, and outcomes in the EORP-AF Pilot General Registry. Am J Med 2015;128:509–18. e2.
    1. Thind M, Holmes DN, Badri M, Pieper KS, Singh A, Blanco RG, Steinberg BA, Fonarow GC, Gersh BJ, Mahaffey KW, Peterson ED, Reiffel JA, Piccini JP, Kowey PR; ORBIT-AF Investigators and Patients. Embolic and other adverse outcomes in symptomatic versus asymptomatic patients with atrial fibrillation (from the ORBIT-AF Registry). Am J Cardiol 2018;122:1677–1683.
    1. Gibbs H, Freedman B, Rosenqvist M, Virdone S, Mahmeed WA, Ambrosio G, Camm AJ, Jacobson B, Jerjes-Sanchez C, Kayani G, Oto A, Panchenko E, Ragy H, Kakkar AK; GARFIELD-AF Investigators. Clinical outcomes in asymptomatic and symptomatic atrial fibrillation presentations in GARFIELD-AF: implications for AF screening. Am J Med 2021;134:893–901.
    1. Arnar DO, Mairesse GH, Boriani G, Calkins H, Chin A, Coats A, Deharo JC, Svendsen JH, Heidbuchel H, Isa R, Kalman JM, Lane DA, Louw R, Lip GYH, Maury P, Potpara T, Sacher F, Sanders P, Varma N, Fauchier L; ESCSD Group; ESD Committee. Management of asymptomatic arrhythmias: a European Heart Rhythm Association (EHRA) consensus document, endorsed by the Heart Failure Association (HFA), Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), Cardiac Arrhythmia Society of Southern Africa (CASSA), and Latin America Heart Rhythm Society (LAHRS). Europace 2019;doi:10.1093/europace/euz046.
    1. Kirchhof P, Camm AJ, Goette A, Brandes A, Eckardt L, Elvan A, Fetsch T, van Gelder IC, Haase D, Haegeli LM, Hamann F, Heidbuchel H, Hindricks G, Kautzner J, Kuck KH, Mont L, Ng GA, Rekosz J, Schoen N, Schotten U, Suling A, Taggeselle J, Themistoclakis S, Vettorazzi E, Vardas P, Wegscheider K, Willems S, Crijns H, Breithardt G; EAST-AFNET 4 Trial Investigators. Early rhythm-control therapy in patients with atrial fibrillation. N Engl J Med 2020;383:1305–1316.
    1. Hohnloser SH, Crijns HJ, van Eickels M, Gaudin C, Page RL, Torp-Pedersen C, Connolly SJ. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009;360:668–678.
    1. Kirchhof P, Breithardt G, Camm AJ, Crijns HJ, Kuck KH, Vardas P, Wegscheider K. Improving outcomes in patients with atrial fibrillation: rationale and design of the Early treatment of Atrial fibrillation for Stroke prevention Trial. Am Heart J 2013;166:442–448.
    1. January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC Jr., Ellinor PT, Ezekowitz MD, Field ME, Furie KL, Heidenreich PA, Murray KT, Shea JB, Tracy CM, Yancy CW. 2019 AHA/ACC/HRS Focused Update of the 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 Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019;140:e125–e151.
    1. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, Kellen JC, Greene HL, Mickel MC, Dalquist JE, Corley SD; Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002. Dec 5;347:1825–1833. 33. doi: 10.1056/NEJMoa021328. PMID: 12466506.
    1. Van Gelder IC, Hagens VE, Bosker HA, Kingma JH, Kamp O, Kingma T, Said SA, Darmanata JI, Timmermans AJM, Tijssen JGP, Crijns HJGM; Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347:1834–1840.
    1. Roy D, Talajic M, Nattel S, Wyse DG, Dorian P, Lee KL, Bourassa MG, Arnold JM, Buxton AE, Camm AJ, Connolly SJ, Dubuc M, Ducharme A, Guerra PG, Hohnloser SH, Lambert J, Le Heuzey JY, O'Hara G, Pedersen OD, Rouleau JL, Singh BN, Stevenson LW, Stevenson WG, Thibault B, Waldo AL; Atrial Fibrillation and Congestive Heart Failure Investigators. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008;358:2667–2677.
    1. Yang E, Tang O, Metkus T, Berger RD, Spragg DD, Calkins HG, Marine JE. The role of timing in treatment of atrial fibrillation: an AFFIRM substudy. Heart Rhythm 2021;18:674–681.
    1. Marrouche NF, Brachmann J, Andresen D, Siebels J, Boersma L, Jordaens L, Merkely B, Pokushalov E, Sanders P, Proff J, Schunkert H, Christ H, Vogt J, Bansch D, Investigators C-A; CASTLE-AF Investigators. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med 2018;378:417–427.
    1. Packer DL, Mark DB, Robb RA, Monahan KH, Bahnson TD, Poole JE, Noseworthy PA, Rosenberg YD, Jeffries N, Mitchell LB, Flaker GC, Pokushalov E, Romanov A, Bunch TJ, Noelker G, Ardashev A, Revishvili A, Wilber DJ, Cappato R, Kuck KH, Hindricks G, Davies DW, Kowey PR, Naccarelli GV, Reiffel JA, Piccini JP, Silverstein AP, Al-Khalidi HR, Lee KL; CABANA Investigators. Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: the CABANA randomized clinical trial. JAMA 2019;321:1261–1274.
    1. Cosedis Nielsen J, Johannessen A, Raatikainen P, Hindricks G, Walfridsson H, Kongstad O, Pehrson S, Englund A, Hartikainen J, Mortensen LS, Hansen PS. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. N Engl J Med 2012;367:1587–1595.
    1. Wilber DJ, Pappone C, Neuzil P, De Paola A, Marchlinski F, Natale A, Macle L, Daoud EG, Calkins H, Hall B, Reddy V, Augello G, Reynolds MR, Vinekar C, Liu CY, Berry SM, Berry DA; ThermoCool AF Trial Investigators. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA 2010;303:333–340.
    1. Andrade JG, Wells GA, Deyell MW, Bennett M, Essebag V, Champagne J, Roux JF, Yung D, Skanes A, Khaykin Y, Morillo C, Jolly U, Novak P, Lockwood E, Amit G, Angaran P, Sapp J, Wardell S, Lauck S, Macle L, Verma A; EARLY-AF Investigators. Cryoablation or drug therapy for initial treatment of atrial fibrillation. N Engl J Med 2021;384:305–315.
    1. Wazni OM, Dandamudi G, Sood N, Hoyt R, Tyler J, Durrani S, Niebauer M, Makati K, Halperin B, Gauri A, Morales G, Shao M, Cerkvenik J, Kaplon RE, Nissen SE; STOP AF First Trial Investigators. Cryoballoon ablation as initial therapy for atrial fibrillation. N Engl J Med 2021;384:316–324.
    1. Metzner A, Suling A, Brandes A, Breithardt G, Camm AJ, Crijns HJGM, Eckardt L, Elvan A, Goette A, Haegeli LM, Heidbuchel H, Kautzner J, Kuck KH, Mont L, Ng GA, Szumowski L, Themistoclakis S, van Gelder IC, Vardas P, Wegscheider K, Willems S, Kirchhof P. Components of AF management and early rhythm control in patients with atrial fibrillation: a detailed analysis of the EAST-AFNET 4 dataset. Europace, in press.
    1. Rienstra M, Vermond RA, Crijns HJ, Tijssen JG, Van Gelder IC RACE Investigators. Asymptomatic persistent atrial fibrillation and outcome: results of the RACE study. Heart Rhythm 2014;11:939–945.
    1. Flaker GC, Belew K, Beckman K, Vidaillet H, Kron J, Safford R, Mickel M, Barrell P; AFFIRM Investigators. Asymptomatic atrial fibrillation: demographic features and prognostic information from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Am Heart J 2005;149:657–663.
    1. Wazni OM, Marrouche NF, Martin DO, Verma A, Bhargava M, Saliba W, Bash D, Schweikert R, Brachmann J, Gunther J, Gutleben K, Pisano E, Potenza D, Fanelli R, Raviele A, Themistoclakis S, Rossillo A, Bonso A, Natale A. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial. JAMA 2005;293:2634–2640.
    1. Mark DB, Anstrom KJ, Sheng S, Piccini JP, Baloch KN, Monahan KH, Daniels MR, Bahnson TD, Poole JE, Rosenberg Y, Lee KL, Packer DL; CABANA Investigators. Effect of catheter ablation vs medical therapy on quality of life among patients with atrial fibrillation: the CABANA randomized clinical trial. JAMA 2019;321:1275–1285.
    1. Wynn GJ, Das M, Bonnett LJ, Gupta D. Quality-of-life benefits of catheter ablation of persistent atrial fibrillation: a reanalysis of data from the SARA study. Europace 2015;17:222–224.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever