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Background: Clinically detected atrial fibrillation (AF) is associated with a significant increase in mortality and other adverse cardiovascular events. Since the advent of effective methods for AF rhythm control, investigators have attempted to determine how much these adverse prognostic AF effects could be mitigated by the restoration of sinus rhythm (SR) and whether the method used mattered., Methods: The CABANA trial (Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation) randomized 2204 AF patients to ablation versus drug therapy, of which 1240 patients were monitored in follow-up using the CABANA ECG rhythm monitoring system. To assess the prognostic benefits of SR, we performed a prespecified analysis using Cox survival modeling with heart rhythm as a time-dependent variable and randomized treatment group as a stratification factor., Results: In the 1240 patient study cohort, 883 (71.2%) had documented AF at some point during their postblanking follow-up. Among the 883 patients, 671 (76.0%) experienced AF within the first year of postblanking follow-up, and 212 (24.0%) experienced their first AF after ≥1 year of postblanking follow-up. The primary CABANA end point (death, disabling stroke, serious bleeding, or cardiac arrest) occurred in 95 (10.8%) of the 883 patients with documented AF and in 29 (8.1%) of the 357 patients with no AF recorded during follow-up. In multivariable time-dependent analysis, the presence of SR (compared with non-SR) was associated with a significantly reduced risk of the primary end point (adjusted hazard ratio, 0.57 [95% CI, 0.38-0.85]; P =0.006; independent of treatment strategy [ablation versus drugs]). Corresponding results for all-cause mortality were adjusted hazard ratio of 0.59 [95% CI, 0.35-1.01]; P =0.053)., Conclusions: In patients in the CABANA trial with detailed long-term rhythm follow-up, increased time in SR was associated with a clinically consequential decrease in mortality and other adverse prognostic events. The predictive value of SR was independent of the therapeutic approach responsible for reducing the burden of detectable AF., Registration: URL: https://clinicaltrials.gov; Unique Identifier: NCT00911508., Competing Interests: Disclosures Dr Packer reports 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 Corp, and Boston Scientific Corp during the conduct of the study; grants from Abbott, Biosense Webster Inc, Boston Scientific Corp, CardioFocus, Medtronic Inc, St. Jude Medical, CardioInsight, NIH, Siemens, Thermedical, Endosense, Robertson Foundation, and Hansen Medical; advisory board without compensation from 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 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 Piccini reports grants from ARCA Biopharma, Boston Scientific, Gilead Sciences, Janssen Pharmaceuticals, Abbott, and Verily; consulting from Allergan, Bayer, Johnson & Johnson, Medtronic, Sanofi, and Philips outside the submitted work. Dr Al-Khalidi reports grants from the NIH/NHLBI and Mayo Clinic during the conduct of the study. Dr Poole reports grants from ATriCure outside the submitted work. Dr Bahnson reports grants from the NIH/NHLBI and Mayo Clinic during the conduct of the study; grants from St. Jude Medical Inc, Abbott Medical, Biosense Webster Inc, Johnson & Johnson, NIH, and Boston Scientific, Corp; and consulting from Cardiofocus Inc, and Ventrix outside the submitted work. Dr Lee reports grants from the NIH/NHLBI and Mayo Clinic, as well as Data Safety Monitoring Board service on studies funded by AstraZeneca, Medtronic, Merck, Amgen, and the Cardiovascular Research Foundation during the conduct of the study. Dr Mark reports grants from NIH/NHLBI and Mayo Clinic during the conduct of the study; grants from Merck, Oxygen Therapeutics, Bristol Myers Squibb, AstraZeneca, University of Calgary, Eli Lilly & Company, AGA Medical, St. Jude Medical, and Tufts University; and personal fees from CeleCor outside the submitted work. The other authors report no conflicts.

Background: In the CABANA trial (Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation), catheter ablation did not significantly reduce the primary end point of death, disabling stroke, serious bleeding, or cardiac arrest compared with drug therapy by intention-to-treat, but did improve the quality of life and freedom from atrial fibrillation recurrence. In the heart failure subgroup, ablation improved both survival and quality of life. Cost-effectiveness was a prespecified CABANA secondary end point., Methods: Medical resource use data were collected for all CABANA patients (N=2204). Costs for hospital-based care were assigned using prospectively collected bills from US patients (n=1171); physician and medication costs were assigned using the Medicare Fee Schedule and National Average Drug Acquisition Costs, respectively. Extrapolated life expectancies were estimated using age-based survival models. Quality-of-life adjustments were based on EQ-5D-based utilities measured during the trial. The primary outcome was the incremental cost-effectiveness ratio, comparing ablation with drug therapy on the basis of intention-to-treat, and assessed from the US health care sector perspective., Results: Costs in the first 3 months averaged $20 794±SD 1069 higher with ablation compared with drug therapy. The cumulative within-trial 5-year cost difference was $19 245 (95% CI, $11 360-$27 170) and the lifetime mean cost difference was $15 516 (95% CI, -$2963 to $35,512) higher with ablation than with drug therapy. The drug therapy arm accrued an average of 12.5 life-years (LYs) and 10.7 quality-adjusted life-years (QALYs). For the ablation arm, the corresponding estimates were 12.6 LYs and 11.0 QALYs. The incremental cost-effectiveness ratio was $57 893 per QALY gained, with 75% of bootstrap replications yielding an incremental cost-effectiveness ratio < $100 000 per QALY gained. With no quality-of-life/utility adjustments, the incremental cost-effectiveness ratio was $183 318 per LY gained., Conclusions: Catheter ablation of atrial fibrillation was economically attractive compared with drug therapy in the CABANA Trial overall at present benchmarks for health care value in the United States on the basis of projected incremental QALYs but not LYs alone.

Background: Observational data suggest that catheter ablation may be safe and effective to treat younger and older patients with atrial fibrillation. No large, randomized trial has examined this issue. This report describes outcomes according to age at entry in the CABANA trial (Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation)., Methods: Patients with atrial fibrillation ≥65 years of age, or <65 with ≥1 risk factor for stroke, were randomly assigned to catheter ablation versus drug therapy. The primary outcome was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Secondary outcomes included all-cause mortality, the composite of mortality or cardiovascular hospitalization, and recurrence of atrial fibrillation. Treatment effect estimates were adjusted for baseline covariables using proportional hazards regression models., Results: Of 2204 patients randomly assigned in CABANA, 766 (34.8%) were <65 years of age, 1130 (51.3%) were 65 to 74 years of age, and 308 (14.0%) were ≥75 years of age. Catheter ablation was associated with a 43% reduction in the primary outcome for patients <65 years of age (adjusted hazard ratio [aHR], 0.57 [95% CI, 0.30-1.09]), a 21% reduction for 65 to 74 years of age (aHR, 0.79 [95% CI, 0.54-1.16]), and an indeterminate effect for age ≥75 years of age (aHR, 1.39 [95% CI, 0.75-2.58]). Four-year event rates for ablation versus drug therapy across age groups, respectively, were 3.2% versus 7.8%, 7.8% versus 9.6%, and 14.8% versus 9.0%. For every 10-year increase in age, the primary outcome aHR increased (ie, less favorable to ablation) an average of 27% (interaction P value=0.215). A similar pattern was seen with all-cause mortality: for every 10-year increase in age, the aHR increased an average of 46% (interaction P value=0.111). Atrial fibrillation recurrence rates were lower with ablation than with drug therapy across age subgroups (aHR 0.47, 0.58, and 0.49, respectively). Treatment-related complications were infrequent for both arms (<3%) regardless of age., Conclusions: We found age-based variations in clinical outcomes for catheter ablation compared with drug therapy, with the largest relative and absolute benefits of catheter ablation in younger patients. No prognostic benefits for ablation were seen in the oldest patients. No differences were found by age in treatment-related complications or in the relative effectiveness of catheter ablation in preventing recurrent atrial arrhythmias., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT00911508.

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Background: In patients with heart failure and atrial fibrillation (AF), several clinical trials have reported improved outcomes, including freedom from AF recurrence, quality of life, and survival, with catheter ablation. This article describes the treatment-related outcomes of the AF patients with heart failure enrolled in the CABANA trial (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation)., Methods: The CABANA trial randomized 2204 patients with AF who were ≥65 years old or <65 years old with ≥1 risk factor for stroke at 126 sites to ablation with pulmonary vein isolation or drug therapy including rate or rhythm control drugs. Of these, 778 (35%) had New York Heart Association class >II at baseline and form the subject of this article. The CABANA trial's primary end point was a composite of death, disabling stroke, serious bleeding, or cardiac arrest., Results: Of the 778 patients with heart failure enrolled in CABANA, 378 were assigned to ablation and 400 to drug therapy. Ejection fraction at baseline was available for 571 patients (73.0%), and 9.3% of these had an ejection fraction <40%, whereas 11.7% had ejection fractions between 40% and 50%. In the intention-to-treat analysis, the ablation arm had a 36% relative reduction in the primary composite end point (hazard ratio, 0.64 [95% CI, 0.41-0.99]) and a 43% relative reduction in all-cause mortality (hazard ratio, 0.57 [95% CI, 0.33-0.96]) compared with drug therapy alone over a median follow-up of 48.5 months. AF recurrence was decreased with ablation (hazard ratio, 0.56 [95% CI, 0.42-0.74]). The adjusted mean difference for the AFEQT (Atrial Fibrillation Effect on Quality of Life) summary score averaged over the entire 60-month follow-up was 5.0 points, favoring the ablation arm (95% CI, 2.5-7.4 points), and the MAFSI (Mayo Atrial Fibrillation-Specific Symptom Inventory) frequency score difference was -2.0 points, favoring ablation (95% CI, -2.9 to -1.2)., Conclusions: In patients with AF enrolled in the CABANA trial who had clinically diagnosed stable heart failure at trial entry, catheter ablation produced clinically important improvements in survival, freedom from AF recurrence, and quality of life relative to drug therapy. These results, obtained in a cohort most of whom had preserved left ventricular function, require independent trial verification. Registration: URL: https://www.clinicaltrials.gov/ct2/show/NCT00911508; Unique identifier: NCT0091150.

Background: Among patients with atrial fibrillation (AF), women are less likely to receive catheter ablation and may have more complications and less durable results. Most information about sex-specific differences after ablation comes from observational data. We prespecified an examination of outcomes by sex in the 2204-patient CABANA trial (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation)., Methods: CABANA randomized patients with AF age ≥65 years or <65 years with ≥1 risk factor for stroke to a strategy of catheter ablation with pulmonary vein isolation versus drug therapy with rate/rhythm control agents. The primary composite outcome was death, disabling stroke, serious bleeding, or cardiac arrest, and key secondary outcomes included AF recurrence., Results: CABANA randomized 819 (37%) women (ablation 413, drug 406) and 1385 men (ablation 695, drug 690). Compared with men, women were older (median age, 69 years versus 67 years for men), were more symptomatic (48% Canadian Cardiovascular Society AF Severity Class 3 or 4 versus 39% for men), had more symptomatic heart failure (42% with New York Heart Association Class ≥II versus 32% for men), and more often had a paroxysmal AF pattern at enrollment (50% versus 39% for men) ( P <0.0001 for all). Women were less likely to have ancillary (nonpulmonary vein) ablation procedures performed during the index procedure (55.7% versus 62.2% in men, P =0.043), and complications from treatment were infrequent in both sexes. For the primary outcome, the hazard ratio for those who underwent ablation versus drug therapy was 1.01 (95% CI, 0.62-1.65) in women and 0.73 (95% CI, 0.51-1.05) in men (interaction P value=0.299). The risk of recurrent AF was significantly reduced in patients undergoing ablation compared with those receiving drug therapy regardless of sex, but the effect was greater in men (hazard ratio, 0.64 [95% CI, 0.51-0.82] for women versus hazard ratio, 0.48 [95% CI, 0.40-0.58] for men; interaction P value=0.060)., Conclusions: Clinically relevant treatment-related strategy differences in the primary and secondary clinical outcomes of CABANA were not seen between men and women, and there were no sex differences in adverse events. The CABANA trial results support catheter ablation as an effective treatment strategy for both women and men. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00911508.

Background: Pharmacological control of rapid ventricular response to atrial fibrillation may be difficult in some patients. Alternative treatments, including curative surgery or atrioventricular (AV) node ablation with pacemaker implantation, have significant potential morbidity. In view of evidence that dual AV nodal physiology may exist in a significant percentage of the population, even in those without AV nodal reentrant tachycardia, we postulated that control of ventricular response might be achieved by radiofrequency (RF) catheter ablation in the region of the AV nodal slow pathway with its short refractory period., Methods and Results: Ten patients underwent attempted AV node modification using a 4-mm-tipped electrode catheter positioned in the middle or posterior septum, between the His bundle and coronary sinus ostium on the tricuspid valve annulus. RF energy was applied at 16 to 30 W for up to 60 seconds, until average ventricular response fell below 100 beats per minute. Reduction of maximal ventricular response below 120 beats per minute was confirmed with atropine 1 mg IV. If required, additional ablations were performed progressively more posteriorly up to the coronary sinus ostium. Patients with successful AV node modification were discharged off AV node-blocking drugs and followed in the clinic at regular intervals. Twenty-four-hour ambulatory ECG recordings and/or treadmill stress tests were obtained before and after ablation for statistical comparison of maximum ventricular rate. Resting average ventricular rate was determined during electrophysiology study before and after ablation. In 7 of 10 patients (70%), maximum ventricular rate was reduced from a mean of 164 +/- 12 to 123 +/- 16 beats per minute (P < .01) and average ventricular rate from a mean of 128 +/- 11 to 83 +/- 10 beats per minute after ablation. Mean minimum ventricular rate was 54 +/- 11 beats per minute after ablation. These 7 patients have remained symptom free from rapid ventricular response for a mean of 14 +/- 8 months (range, 1 to 22). Three remain off all AV node-blocking drugs, 3 remain on digoxin alone, which was previously ineffective, and 1 remains on a beta-blocker for angina. In the 3 patients who did not respond to AV node modification, complete AV node ablation and permanent pacemaker implantation was performed in 2 and DC cardioversion after amiodarone loading was performed in 1., Conclusions: RF catheter modification of AV node conduction is effective in controlling rapid ventricular response to atrial fibrillation in a significant percentage of medically refractory patients. A possible mechanism of RF modification of AV node conduction is AV nodal slow pathway ablation. Large-scale clinical trials will be needed to determine the overall efficacy and safety of this technique.

Background: Recent studies of human type 1 atrial flutter demonstrated reentry in the right atrium and an area of slow conduction in the low posteroseptal right atrium. Direct-current catheter ablation of this area has been only moderately successful in preventing recurrence. Therefore, we performed endocardial activation mapping and entrainment pace mapping during atrial flutter to determine the critical site for radiofrequency ablation of this arrhythmia., Methods and Results: Twelve consecutive patients (seven men and five women; age, 21-73 years) with type 1 atrial flutter (mean cycle length, 253 +/- 39 msec) underwent right atrial endocardial activation and entrainment pace mapping using standard transvenous catheter techniques to localize the atrial flutter reentrant circuit, the area of slow conduction, and the exit site from the area of slow conduction. Upon identifying appropriate sites, radiofrequency energy (16-29 W) was applied via a 4-mm tipped catheter. Activation mapping of atrial flutter revealed a counterclockwise reentrant wave front originating just inferior or posterior to the coronary sinus ostium, proceeding superiorly in the atrial septum to the right atrial free wall, then inferiorly toward the tricuspid annulus and finally medially between the inferior vena cava and the tricuspid annulus, where low-amplitude fragmented electrical activity was noted. Entrainment pace mapping from this area produced an exact P wave match to atrial flutter on 12-lead ECG with a long (greater than 40 msec) stimulus-to-P interval indicating slow conduction, whereas pacing just inferior or posterior to the coronary sinus ostium produced an exact P wave match with a short stimulus-to-P interval (less than 40 msec), presumably identifying the exit site from the area of slow conduction. Radiofrequency energy (one to 14 applications) was effective in terminating and preventing reinduction of atrial flutter in 10 patients. In two patients, atrial flutter was not terminated during radiofrequency energy application but during subsequent pacing attempts. Sites where ablation was successful, located just inferior or posterior to the coronary sinus ostium, were characterized by discrete electrograms with activation times of -20 to -50 msec before P wave onset and exact entrainment pace maps with a stimulus-to-P interval of 20 to 40 msec, consistent with the exit site from the area of slow conduction. Follow-up (mean, 16 +/- 9 weeks; range, 2-31 weeks) revealed recurrence of the original atrial flutter in two patients, one of whom underwent repeat ablation without further recurrence, self-limited infrequent recurrence of a new atrial flutter or atrial fibrillation in three suppressed by beta-blocker or digoxin, and no recurrence in seven., Conclusions: 1) Radiofrequency energy applied to a critical area in the atrial flutter reentrant circuit, inferior or posterior to the coronary sinus ostium, will terminate and prevent arrhythmia reinduction. 2) Long-term follow-up in a larger series of patients will be required to confirm efficacy of this technique, although short-term results look promising.

Substance P inhibits renin secretion. This polypeptide is a transmitter in primary afferent neurons and is released from the peripheral as well as the central portions of these neurons. It is present in afferent nerves from the kidneys. Neuropeptide Y, which is a cotransmitter with norepinephrine and epinephrine, is found in sympathetic neurons that are closely associated with and presumably innervate the juxtagolmerular cells. Its effect on renin secretion is unknown, but it produces renal vasoconstriction and natriuresis. Vasoactive intestinal polypeptide (VIP) is a cotransmitter with acetylocholine in cholinergic neurons, and this polypeptide stimulates renin secretion. We cannot find any evidence for its occurence in neurons in the kidneys, but various stimuli increase plasma VIP to levels comparable to those produced by doses of exogenous VIP which stimulated renin secretion. Neostigmine increases plasma VIP and plasma renin activity, and the VIP appears to be responsible for the increase in renin secretion, since the increase is not blocked by renal denervation or propranolol. Stimulation of various areas in the brain produces sympathetically mediated increases in plasma renin activity associated with increases in blood pressure. However, there is pharmacological evidence that the renin response can be separated from the blood pressure response. In anaesthetized dogs, drugs that increase central serotonergic discharge increase renin secretion without increasing blood pressure. In rats, activation of sertonergic neurons in the dorsal raphe nucleus increases renin secretion by a pathway that projects from this nucleus to the ventral hypothalamus, and from there to the kidneys via the sympathetic nervous system. The serotonin releasing drug parachloramphetamine also increases plasma VIP, but VIP does not appear to be the primary mediator of the renin response. There is preliminary evidence that the serotonergic neurons in the dorsal raphe nucleus are part of the pathway by which psychosocial stimuli increase renin secretion.