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

Abstract

Importance: Catheter ablation is effective in restoring sinus rhythm in atrial fibrillation (AF), but its effects on long-term mortality and stroke risk are uncertain.

Objective: 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.

Interventions: 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.

Results: 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.

Trial registration: ClinicalTrials.gov Identifier: NCT00911508.

Conflict of interest statement

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.

Figures

Figure 1.. Randomization and Patient Flow in the CABANA Trial

aSites were not required to provide screening logs during the recruitment phase; thus, the number of patients assessed for eligibility is not available. bTwenty five patients underwent repeat catheter ablation during the blanking period; 190 patients had at least 1 repeat catheter ablation during the postblanking period for a total of 215. cOutcomes of patients who did not complete the study (ie, withdrew consent or were lost to follow-up) were included to the point of consent withdrawal or final contact. Primary and key secondary end points were analyzed using time-to-event methodology; thus, all available follow-up information was used. For patients who did not complete the study and did not experience an outcome event, their time-to-event measure was censored at the last contact date. There was no imputation of outcome events. At the end of the trial, a publicly available death registry search was performed for patients enrolled in North America who were lost or withdrew from the trial.

Figure 2.. Kaplan-Meier Estimates of the Incidence of the Primary End Point

Kaplan-Meier estimates of the cumulative risk of death, disabling stroke, serious bleeding, or cardiac arrest (primary end point by intention-to-treat analysis). The median (25th, 75th percentile) length of patient follow-up was 4.1 years (2.5, 5.1) in the catheter ablation group and 4.0 years (2.5, 5.2) in the drug therapy group.

Figure 3.. Kaplan-Meier Estimates of All-Cause Mortality and Mortality or Cardiovascular Hospitalization by Intention-to-Treat Analysis

A, The median (25th, 75th percentiles) length of patient follow-up was 4.1 years (2.5, 5.1) in the catheter ablation group and 4.0 years (2.5, 5.2) in the drug therapy group. B, The median (25th, 75th percentiles) length of patient follow-up was 4.1 years (2.5, 5.1) in the catheter ablation group and 4.0 years (2.5, 5.2) in the drug therapy group.

Figure 4.. Primary End Point Subgroup Analysis (Intention to Treat)

The squares represent the hazard ratios and the bars indicate the 95% CIs. AF indicates atrial fibrillation; CHA2DS2-VASc, congestive heart failure, hypertension, age ≥75 years (doubled), diabetes, stroke/transient ischemic attack/thromboembolism (doubled), vascular disease (prior myocardial infarction, peripheral artery disease, or aortic plaque), age 65-75 years, sex category (female); LVH, left ventricular hypertrophy; NYHA, New York Heart Association. aMinority = Hispanic or Latino or nonwhite race. Minority status was determined by the site investigator in conjunction with the patient based on predefined categories as required by the National Institutes of Health (NIH) using NIH-specified categories. bParoxysmal = AF episodes lasting ≥1 hour in duration that terminate spontaneously within 7 days or cardioversion is performed within 48 hours of AF onset. Persistent = AF episode sustained for ≥7 days or cardioversion is performed more than 48 hours after AF onset. Long-standing persistent = continuous AF >1 year in duration. cOn a scale of I to IV, with I indicating the least severe and IV, the most severe symptoms of heart failure. dOn a scale of 0 to 9, with 0 indicating the lowest risk of stroke and 9, the highest risk of stroke. eCalculated as weight in kilograms divided by height in meters squared.

Figure 5.. Kaplan-Meier Estimates of the Primary End Point by Per-Protocol Analysis

Kaplan-Meier estimates of the cumulative risk of death, disabling stroke, serious bleeding, or cardiac arrest (primary end point) by 6-month (A) and 12-month (B) per-protocol analysis. Figure includes patients randomized to catheter ablation who were ablated within 6 months (A) or 12 months (B) after randomization. It also includes all patients randomized to drug therapy, with follow-up censored at crossover to ablation. A, The median (25th, 75th percentiles) length of patient follow-up was 4.1 years (2.6, 5.2) in the catheter ablation group and 4.0 years (2.5, 5.2) in the drug therapy group. B, The median (25th, 75th percentiles) length of patient follow-up was 4.2 years (2.6, 5.2) in the catheter ablation group and 4.0 years (2.5, 5.2) in the drug therapy group.

Figure 6.. Recurrent Atrial Fibrillation After Blanking by Intention-to-Treat Analysis

Freedom from recurrence of atrial fibrillation following the blanking period in 1240 patients who used the study electrocardiogram event recorders (intention-to-treat analysis with death as a competing risk). The median (25th, 75th percentiles) length of patient follow-up was 4.3 years (2.8, 5.0) in the catheter ablation group and 4.3 years (2.7, 5.3) in the drug therapy group.