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Among patients with atrial fibrillation, what is the effect of catheter ablation, compared with medical therapy, on cardiovascular events and mortality?
In this randomized clinical trial involving 2204 patients with atrial fibrillation, catheter ablation, compared with medical therapy, did not significantly reduce the primary composite end point of death, disabling stroke, serious bleeding, or cardiac arrest (8.0% vs 9.2%, respectively; hazard ratio, 0.86).
Among patients with atrial fibrillation, catheter ablation, compared with medical therapy, did not significantly reduce the primary composite outcome.
Catheter ablation is effective in restoring sinus rhythm in atrial fibrillation (AF), but its effects on long-term mortality and stroke risk are uncertain.
To determine whether catheter ablation is more effective than conventional medical therapy for improving outcomes in AF.
Design, Setting, and Participants
The Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation trial is an investigator-initiated, open-label, multicenter, randomized trial involving 126 centers in 10 countries. A total of 2204 symptomatic patients with AF aged 65 years and older or younger than 65 years with 1 or more risk factors for stroke were enrolled from November 2009 to April 2016, with follow-up through December 31, 2017.
The catheter ablation group (n = 1108) underwent pulmonary vein isolation, with additional ablative procedures at the discretion of site investigators. The drug therapy group (n = 1096) received standard rhythm and/or rate control drugs guided by contemporaneous guidelines.
Main Outcomes and Measures
The primary end point was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Among 13 prespecified secondary end points, 3 are included in this report: all-cause mortality; total mortality or cardiovascular hospitalization; and AF recurrence.
Of the 2204 patients randomized (median age, 68 years; 37.2% female; 42.9% had paroxysmal AF and 57.1% had persistent AF), 89.3% completed the trial. Of the patients assigned to catheter ablation, 1006 (90.8%) underwent the procedure. Of the patients assigned to drug therapy, 301 (27.5%) ultimately received catheter ablation. In the intention-to-treat analysis, over a median follow-up of 48.5 months, the primary end point occurred in 8.0% (n = 89) of patients in the ablation group vs 9.2% (n = 101) of patients in the drug therapy group (hazard ratio [HR], 0.86 [95% CI, 0.65-1.15]; P = .30). Among the secondary end points, outcomes in the ablation group vs the drug therapy group, respectively, were 5.2% vs 6.1% for all-cause mortality (HR, 0.85 [95% CI, 0.60-1.21]; P = .38), 51.7% vs 58.1% for death or cardiovascular hospitalization (HR, 0.83 [95% CI, 0.74-0.93]; P = .001), and 49.9% vs 69.5% for AF recurrence (HR, 0.52 [95% CI, 0.45-0.60]; P < .001).
Conclusions and Relevance
Among patients with AF, the strategy of catheter ablation, compared with medical therapy, did not significantly reduce the primary composite end point of death, disabling stroke, serious bleeding, or cardiac arrest. However, the estimated treatment effect of catheter ablation was affected by lower-than-expected event rates and treatment crossovers, which should be considered in interpreting the results of the trial.
ClinicalTrials.gov Identifier: NCT00911508
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Corresponding Author: Douglas L. Packer, MD, Mayo Clinic/St Marys, 1216 Second St SW, Al 2-416, Rochester, MN 55902 (firstname.lastname@example.org).
Accepted for Publication: February 14, 2019.
Published Online: March 15, 2019. doi:10.1001/jama.2019.0693
Author Contributions: Drs Packer and Lee had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Packer, Mark, Robb, Monahan, Bahnson, Poole, Rosenberg, Mitchell, Flaker, Bunch, Wilber, Hindricks, Piccini, Kowey, Naccarelli, Lee.
Acquisition, analysis, or interpretation of data: Packer, Mark, Monahan, Bahnson, Noseworthy, Jeffries, Mitchell, Flaker, Pokushalov, Romanov, Bunch, Noelker, Ardashev, Revishvili, Wilber, Cappato, Kuck, Hindricks, Davies, Piccini, Kowey, Reiffel, Silverstein, Al-Khalidi, Lee.
Drafting of the manuscript: Packer, Mark, Monahan, Bahnson, Silverstein, Lee.
Critical revision of the manuscript for important intellectual content: Packer, Mark, Robb, Monahan, Bahnson, Poole, Noseworthy, Rosenberg, Jeffries, Mitchell, Flaker, Pokushalov, Romanov, Bunch, Noelker, Ardashev, Revishvili, Wilber, Cappato, Kuck, Hindricks, Davies, Piccini, Kowey, Naccarelli, Reiffel, Silverstein, Al-Khalidi, Lee.
Statistical analysis: Packer, Mark, Jeffries, Silverstein, Al-Khalidi, Lee.
Obtained funding: Packer, Mark, Robb, Lee.
Administrative, technical, or material support: Packer, Monahan, Bahnson, Noseworthy, Rosenberg, Mitchell, Bunch, Noelker, Davies, Piccini, Lee.
Supervision: Packer, Monahan, Rosenberg, Flaker, Romanov, Bunch, Ardashev, Lee.
Conflict of Interest Disclosures: Dr Packer reported receiving grants from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI), St Jude Medical Corporation and Foundation, Biosense Webster Inc, Medtronic Inc, and Boston Scientific Corp during the conduct of the study and receiving grants from Abbott, Biosense Webster Inc, Boston Scientific Corp, CardioFocus, Medtronic Inc, St Jude Medical, CardioInsight, the NIH, Siemens, Thermedical, Endosense, Robertson Foundation, and Hansen Medical; serving on the advisory board without compensation for Abbott, Biosense Webster Inc, Boston Scientific Corp, CardioFocus, Medtronic Inc, St Jude Medical, Spectrum Dynamics, Siemens, Thermedical, Johnson & Johnson, and SigNum Preemptive Healthcare Inc; speaking with honorarium from Biotronik and MediaSphere Medical LLC; and receiving royalties from Wiley & Sons, Oxford, and St Jude Medical. Dr Packer and Mayo Clinic jointly have equity in a privately held company, External Beam Ablation Medical Devices, outside the submitted work. In addition, Dr Packer has mapping technologies with royalties paid. Dr Mark reported receiving grants from the NIH/NHLBI and Mayo Clinic during the conduct of the study and grants from Merck, Oxygen Therapeutics, Bristol-Myers Squibb, AstraZeneca, the University of Calgary, Eli Lilly & Company, AGA Medical, St Jude Medical, and Tufts University and personal fees from CeleCor outside the submitted work. Dr Robb reported receiving grants from the NIH/NHLBI, St Jude Medical Corporation and Foundation, Biosense Webster Inc, Medtronic Inc, and Boston Scientific Corp during the conduct of the study. Dr Robb has a patent for a 4D mapping system with royalties paid to Endocardial Solutions outside the submitted work. Ms Monahan reported receiving grants from the NIH/NHLBI, St Jude Foundation and Corporation, Biosense Webster Inc, Medtronic Inc, and Boston Scientific Corp during the conduct of the study; consulting without compensation from Biosense Webster Inc; and receiving personal fees from Thermedical outside the submitted work. Dr Bahnson reported receiving grants from the NIH/NHLBI and Mayo Clinic during the conduct of the study and grants from St Jude Medical Inc, Abbott Medical, Medtronic Inc, Biosense Webster Inc, Johnson & Johnson, the NIH, and Boston Scientific Corp; and consulting fees from Cardiofocus Inc and Ventrix outside the submitted work. Dr Bahnson has patents pending for a catheter for intracardiac imaging and intracardiac electrogram signal analysis. Dr Poole reported receiving grants from ATriCure outside the submitted work. Dr Noseworthy reported receiving grants from the NHLBI outside the submitted work and being a co–principal investigator in the Pairing Observational and Patient-Level Clinical Trial Data to Assess Cardiovascular Risk Reduction With Catheter Ablation for Atrial Fibrillation study. Dr Mitchell reported receiving expense reimbursement from the NIH during the conduct of the study and personal fees from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer, Servier, and Medtronic Inc and grants from Population Health Research Institute, Hamilton, Ontario, Canada, outside the submitted work. Dr Flaker reported receiving grants from Daiichi Sankyo and Janssen Pharmaceutical and grants and personal fees from Boehringer-Ingelheim, Bristol-Myers Squibb, and Pfizer outside the submitted work. Dr Bunch reported receiving grants from Boehringer-Ingelheim outside the submitted work. Dr Wilber reported receiving grants and personal fees from Biosense Webster Inc and Medtronic Inc and grants from Abbott and Sentre Heart outside the submitted work. Dr Cappato reported receiving grants from Boston Scientific Corp, Medtronic Inc, Daiichi Sankyo, St Jude Medical, Bayer, and Pfizer. Dr Kuck reported receiving personal fees from Medtronic Inc, Boston Scientific Corp, Abbott, Edwards Lifesciences, and Biosense Webster Inc outside the submitted work. Dr Hindricks reported receiving grants from Abbott and Boston Scientific Corp, directly to Heart Centre Leipzig, during the conduct of the study. Dr Davies reported receiving personal fees from Medtronic Inc outside the submitted work. Dr Kowey reported receiving personal fees from Medtronic Inc and personal fees from and equity interest in Biotelemetry outside the submitted work. Dr Naccarelli reported receiving grants and personal fees from Janssen and personal fees from GlaxoSmithKline, Aceion, Omeicos, Sanofi, and Portola outside the submitted work. Dr Reiffel reported receiving grants and personal fees from Medtronic Inc and personal fees from Gilead, Janssen/Johnson & Johnson, Portola, Acension, InCardia Therapeutics, Roivant, and Sanofi outside the submitted work. Dr Piccini reported receiving grants from ARCA Biopharma, Boston Scientific Corp, Gilead Sciences, Janssen Pharmaceuticals, Abbott, and Verily and consulting fees from Abbott, Allergan, Bayer, Biotronik, Johnson & Johnson, Medtronic Inc, Sanofi, and Philips outside the submitted work. Dr Al-Khalidi reported receiving grants from the NIH/NHLBI and Mayo Clinic during the conduct of the study. Dr Lee reported receiving grants from the NIH/NHLBI, Mayo Clinic, St Jude Medical Foundation and Corporation, Biosense Webster Inc, Medtronic Inc, and Boston Scientific Corp and serving on data and safety monitoring boards on studies funded by AstraZeneca, Medtronic Inc, Merck, Amgen, and the Cardiovascular Research Foundation during the conduct of the study. No other disclosures were reported.
Funding/Support: This research was funded by awards from the NIH. Dr Packer was supported by NIH grant U01HL089709. Dr Lee was supported by NIH grant U01HL089786. Dr Mark was supported by NIH grant U01HL089907. Dr Robb was supported by NIH grant U01HL089645. This research was also funded by St Jude Medical Foundation and Corporation, Biosense Webster Inc, Medtronic Inc, and Boston Scientific Corp.
Role of the Funder/Sponsor: The NIH established an independent data and safety monitoring board to monitor safety but had no role in the design of the study; collection, management, and interpretation of the data; preparation of the manuscript; or decision to submit the manuscript for publication. St Jude Medical Foundation and Corporation, Biosense Webster Inc, Medtronic Inc, and Boston Scientific Corp had no role in the design of the study; collection, management, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.
Clinical Site Principal Investigators and Institutions: (Listed in descending order of the number of randomized patients): Evgeny Pokushalov, Alexander Romanov, E. Meshalkin National Medical Research Center of the Ministry of Health of the Russian Federation, Novosibirsk, Russian Federation (147); T. Jared Bunch, Intermountain Medical Center, Murray, Utah (139); Tristram Bahnson, Duke University Medical Center, Durham, North Carolina (133); Georg Noelker, Herz-und Diabeteszentrum NRW, Bad Oeynhausen, Germany (98); Douglas Packer, Mayo Clinic, Rochester, Minnesota (93); Gerhard Hindricks, Herzzentrum Leipzig, Leipzig, Germany (88); Andrey Ardashev, Clinical Hospital No. 83 under the Federal Medical and Biological Agency, Moscow, Russia (66); Amiran Revishvili, George Matsonashvili, Bakoulev Scientific Center for Cardiovascular Surgery, Moscow, Russia (52); Pugazhendhi Vijayaraman, Geisinger Wyoming Valley Medical Center, Wilkes-Barre, Pennsylvania (43); Huseyin Ince, Universitat Rostock, Rostock, Germany (previously Dietmar Baensch) (42); Christopher Piorkowski, Technische Universitat Dresden, Dresden, Germany (41); Thomas Neumann, Kerckhoff Klinik, Bad Nauheim, Germany (40); George Veenhuyzen, University of Calgary, Calgary, Alberta, Canada (39); Anil Gehi, University of North Carolina at Chapel Hill (previously Paul Mounsey) (38); David Wilber, Loyola University Medical Center, Maywood, Illinois (36); Felix Sogade, Georgia Arrhythmia Consultants, Macon (34); Carlo Pappone, Policlinico San Donato Center of Clinical Arrhythmia and Electrophysiology, San Donato Milanese, Italy (previously Riccardo Cappato) (32); Adam Berman, Georgia Regents University, Augusta (31); Alaa Shalaby, V.A. Pittsburgh Healthcare System, Pittsburgh, Pennsylvania (25); Karl-Heinz Kuck, Asklepios Klinik Saint George, Hamburg, Germany (25); Blair Halperin, Providence Saint Vincent Medical Center, Portland, Oregon (25); Venkat Tholakanahalli, Minneapolis V.A. Medical Center, Minneapolis, Minnesota (24); Eugen Palma, Montefiore Medical Center, New York, New York (24); John Holshouser, The Sanger Clinic, PA, Charlotte, North Carolina (24); Nitish Badhwar, University of California at San Francisco Medical Center (23); Haroon Rashid, Virginia Hospital Center–Arlington (23); Craig Cameron, Oklahoma Heart Institute, Tulsa (22); John Hummel, The Ohio State University Medical Center, Columbus (22); Pablo Saavedra, Vanderbilt University Medical Center, Nashville, Tennessee (previously Dawood Darbar) (21); J. Brian Deville, The Heart Hospital Baylor Plano, Plano, Texas (21); Julian Chun, Cardioaniologisches Centrum Bethanien, Frankfurt, Germany (20); Javier Roman-Gonzalez, South Texas Cardiovascular Consultants, San Antonio (20); Stephen Willems, Universitares Herzzentrum Hamburg, Hamburg, Germany (20); Hasan Garan, Columbia University Medical Center, New York, New York (20); Eric Michael Crespo, Hartford Hospital, Hartford, Connecticut (19); Peter Cheung, Scott and White Memorial Hospital, Temple, Texas (previously David Fitzgerald) (18); Gerian Groenefeld, Asklepios Klinik Barmbek, Hamburg, Germany (17); Claudio Schuger, Henry Ford Hospital, Detroit, Michigan (16); Tariq Salam, Cardiac Study Center, Tacoma, Washington (16); Yanzong Yang, The First Affiliated Hospital of Dalian Medical University, Dalian, China (15); Carlo Pappone, Maria Cecilia Hospital, Cotignola, Italy (15); Dan Wichterle, Charles University, Prague 2, Czech Republic (15); Johannes Brachmann, Klinikum Coburg, Coburg, Germany (15); Josef Kautzner, Clinic of Cardiology IKEM Medical Institute, Prague 4, Czech Republic (15); John Jayachandran, Baylor All Saints Medical Center, Fort Worth, Texas (15); Young-Hoon Kim, Korea University Anam Hospital, Seoul, Korea (14); Christopher Cole, Penrose Saint Francis Health Services, Colorado Springs, Colorado (14); Bengt Herweg, University of South Florida, Tampa (13); Martin Lowe, The Heart Hospital, London, United Kingdom (12); Anne Dougherty, University of Texas Health Science Center at Houston (previously Bharat Kantharia and Nada Memon) (12); Sergey Popov, Scientific Research Institute of Cardiology of Siberian Dept of Russian Academy of Medical Sciences, Tomsk, Russia (11); Martin Lowe, Saint Bartholomew’s Hospital, London, United Kingdom (previously Richard Schilling) (11); Stefan Spitzer, Praxisklinik Herz and GefaBe, Dresden, Germany (11); Robert Bernstein, Sentara Norfolk General Hospital, Norfolk, Virginia (11); Jay Simonson, Park Nicollet Heart and Vascular Center/Methodist Hospital, St Louis Park, Minnesota (11); Eric Buch, University of California Los Angeles (10); Shulin Wu, Guangdong Provincial People’s Hospital, Guangzhou, China (10); Mohammed Khan, Alexian Brothers Medical Center, Elk Grove Village, Illinois (10); Timothy Shinn, Saint Joseph Mercy Hospital, Ann Arbor, Michigan (previously James Kappler) (10); Petr Neuzil, Na Homolce Hospital, Prague, Czech Republic (9); James Mangrum, University of Virginia Health System, Charlottesville (9); Hugh Calkins, Johns Hopkins Hospital, Baltimore, Maryland (9); Mario Gonzalez, Penn State University Cardiovascular Center, Hershey, Pennsylvania (9); Moussa Mansour, Massachusetts General Hospital, Boston (9); Markus Zabel, Georg-August-University, Goettingen, Germany (8); Jonathan Kalman, Royal Melbourne Hospital, Parkville, Australia (8); Jose Sanchez, Saint John’s Mercy Heart Hospital, St Louis, Missouri (8); Steven Rothman, Lankenau Medical Center, Wynnewood, Pennsylvania (8); Anil Bhandari, Good Samaritan Hospital, Los Angeles, California (8); Cynthia Tracy, George Washington University Medical Center, Washington, DC (8); Raul Mitrani, University of Miami Health System, Miami, Florida (7); Vicken Vorperian, Waukesha Memorial Hospital, Waukesha, Wisconsin (7); Derek Connelly, Golden Jubilee Hospital, Glasgow, United Kingdom (7); Darryl Wells, Swedish Medical Center–Providence Campus, Seattle, Washington (7); Chang-Sheng Ma, Beijing Anzhen Hospital, Beijing, China (7); Atul Verma, Southlake Regional Health Centre, Newmarket, Ontario, Canada (7); S. Luke Kusmirek, Drexel University College of Medicine, Philadelphia, Pennsylvania (7); Melissa Robinson, University of Washington Medical Center, Seattle (previously Robert Rho and Mohan Viswanathan) (7); Donald Rubenstein, Greenville Hospital System University Medical Center, Greenville, South Carolina (6); Emilio Vanoli, Policlinico Multimedical Cardiology and Arrhythmia Centre, Milan, Italy (previously Annibale Montenero) (6); Shu Zhang, Fuwai Hospital, Beijing, China (6); Jennifer Cummings, The University of Toledo, Toledo, Ohio (previously Mohammed Kanjwal) (6); Mohan Viswanathan, Stanford University Medical Center, Stanford, California (previously Amin Al Ahmad and Paul Zei) (6); George Monir, Florida Hospital, Orlando (6); Francis Marchlinski, University of Pennsylvania Health System, Philadelphia (6); Jay Franklin, Baylor Heart and Vascular Hospital, Dallas, Texas (previously Robert Kowal) (6); Bruce Koplan, Brigham and Women’s Hospital, Boston, Massachusetts (previously Gregory Michaud) (6); Prashanthan Sanders, Royal Adelaide Hospital, Adelaide, South Australia, Australia (5); Eric Rashba, Stony Brook University Medical Center, Stony Brook, New York (5); Mark Gallagher, Saint George’s Hospital Medical School, London, United Kingdom (5); Bernd Gonska, Saint Vincentius-Kliniken, Karlsruhe, Germany (5); Minglong Chen, First Affiliated Hospital of Nanjing Medical University, Nanjing, China (5); Peter Leong-Sit, University of Western Ontario–London Health Sciences Centre, London, Ontario, Canada (5); John Zimmerman, Hackensack University Medical Center, Hackensack, New Jersey (5); Nayer Pezeshkian, University of California Davis Medical Center, Sacramento (5); Andrew Cohen, The Medical Center of Aurora, Aurora, Colorado (5); Saulius Kalvaitis, Saint Louis Heart and Vascular, St Louis, Missouri (4); David Davies, Saint Mary’s Hospital, London, United Kingdom (4); Martin Borggrefe, University Hospital of Mannheim, Mannheim, Germany (4); Hui-Nam Pak, Yonsei University Severance Hospital, Seoul, Korea (4); Andrea Russo, Cooper University Hospital, Camden, New Jersey (4); Charles Henrikson, Oregon Health and Science University, Portland (previously Jack Kron) (4); Gerald Greer, Arkansas Cardiology, PA, Little Rock (4); James Coromilas, Robert Wood Johnson University Hospital, New Brunswick, New Jersey (3); Farhat Khairallah, Tallahassee Memorial Hospital, Tallahassee, Florida (3); Guillermo Sosa-Suarez, Albany Associates in Cardiology, Albany, New York (3); Bruce Lindsay, Cleveland Clinic Foundation, Cleveland, Ohio (3); Westby Fisher, North Shore University Health System/Evanston Hospital, Evanston, Illinois (3); Steven Bailin, Mercy Medical Center, Des Moines, Iowa (3); Andy Tran, Scottsdale Healthcare, Scottsdale, Arizona (2); Zdenek Starek, Saint Anne’s University Hospital, ICRC, Brno, Czech Republic (2); Mark Preminger, The Valley Hospital, Ridgewood, New Jersey (2); Robert Sheppard, Northside Hospital and Heart Institute, St Petersburg, Florida (2); Alexandru Costea, University of Cincinnati Medical Center, Cincinnati, Ohio (2); Kenneth Ellenbogen, Virginia Commonwealth University Medical Center, Richmond (2); Thomas Arentz, Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany (1); Roberto De Ponti, Ospedale di Circolo e Fondazione Macchi, Varese, Italy (1); Ryan Aleong, University of Colorado Hospital, Aurora (1); Byron Colley III, Jackson Heart Clinic, Jackson, Mississippi (1); Khawaja Baig, Medisync, Cincinnati, Ohio (1); Kousik Krishnan, Rush University Medical Center, Chicago, Illinois (1); Syamkumar Divakara Menon, Hamilton Health Sciences, Hamilton, Ontario, Canada (previously Carlos Morillo) (1); Tony Simmons, Wake Forest University Health Sciences, Winston-Salem, North Carolina (1); Gregory Bruce, Memorial Health Care System, Chattanooga, Tennessee (1); Larry Chinitz, Tisch Hospital (New York University Langone Medical Center), New York (1); Andrea Natale, Texas Cardiac Arrhythmia, Austin (1); and Riccardo Cappato, IRCCS Istituto Clinico Humanitas, Milano, Italy.
Disclaimer: The content of this article does not necessarily represent the views of the NHLBI or the Department of Health and Human Services.
Meeting Presentation: This study was presented at the Annual Heart Rhythm Society Scientific Sessions; May 10, 2018; Boston, Massachusetts.
Data Sharing Statement: See Supplement 4.
Additional Contributions: We are grateful to all patients and their families for their participation in this study, the study sites, and the study monitors. Editorial assistance with preparation of the manuscript was provided by Jacqueline Crowson, Mayo Clinic, Rochester, Minnesota, without personal compensation. Statistical and data coordinating center project leadership was provided by Beth Martinez, MS, PMP, Durham, North Carolina, without personal compensation.
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