Silverstein, A

Importance Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. Objective To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. Design, Setting, and Participants This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. Interventions Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. Main Outcomes and Measures Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. Results A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, −0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, −0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. Conclusions and Relevance This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. Trial Registration ClinicalTrials.gov Identifier: NCT05965739 .

Background Women with atrial fibrillation (AF) demonstrate more AF‐related symptoms and worse quality of life (QOL). Whether increased use of ablation in women reduces sex‐related QOL differences is unknown. Sex‐related outcomes for ablation versus drug therapy was a prespecified analysis in the CABANA (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation) trial. Methods and Results Symptoms were assessed periodically over 60 months with the Mayo AF‐Specific Symptom Inventory (MAFSI) frequency score, and QOL was assessed with the Atrial Fibrillation Effect on Quality of Life (AFEQT) summary and component scores. Women had lower baseline QOL scores than men (mean AFEQT scores 55.9 and 65.6, respectively). Ablation patients improved more than drug therapy patients with similar treatment effect by sex: AFEQT 12‐month mean adjusted treatment difference in women 6.1 points (95% CI, 3.5–8.6) and men 4.9 points (95% CI, 3.0–6.9). Participants with baseline AFEQT summary scores <70 had greater QOL improvement, with a mean treatment difference at 12 months of 7.6 points for women (95% CI, 4.3–10.9) and 6.4 points for men (95% CI, 3.3–9.4). The mean adjusted difference in MAFSI frequency score between women randomized to ablation versus drug therapy at 12 months was −2.5 (95% CI, −3.4 to −1.6); for men, the difference was −1.3 (95% CI, −2.0 to −0.6). Conclusions Compared with drug therapy for AF, ablation resulted in more QOL improvement in both sexes, primarily driven by improvements in those with lower baseline QOL. Ablation did not eliminate the AF‐related QOL gap between women and men. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00911508.

Abstract Aims Influence of atrial fibrillation (AF) type on outcomes seen with catheter ablation vs. drug therapy is incompletely understood. This study assesses the impact of AF type on treatment outcomes in the Catheter Ablation vs. Antiarrhythmic Drug Therapy for Atrial Fibrillation Trial (CABANA). Methods and results CABANA randomized 2204 patients ≥65 years old or &lt;65 with at least one risk factor for stroke to catheter ablation or drug therapy. Of these, 946 (42.9%) had paroxysmal AF (PAF), 1042 (47.3%) had persistent AF (PersAF), and 215 (9.8%) had long-standing persistent AF (LSPAF) at baseline. The primary endpoint was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Symptoms were measured with the Mayo AF-Specific Symptom Inventory (MAFSI), and quality of life was measured with the Atrial Fibrillation Effect on Quality of Life (AFEQT). Comparisons are reported by intention to treat. Compared with drug therapy alone, catheter ablation produced a 19% relative risk reduction in the primary endpoint for PAF {adjusted hazard ratio [aHR]: 0.81 [95% confidence interval (CI): 0.50, 1.30]}, and a 17% relative reduction for PersAF (aHR: 0.83, 95% CI: 0.56, 1.22). For LSPAF, the ablation relative effect was a 7% reduction (aHR: 0.93, 95% CI: 0.36, 2.44). Ablation was more effective than drug therapy at reducing first AF recurrence in all AF types: by 51% for PAF (aHR: 0.49, 95% CI: 0.39, 0.62), by 47% for PersAF (aHR: 0.53, 95% CI: 0.43,0.65), and by 36% for LSPAF (aHR 0.64, 95% CI 0.41,1.00). Ablation was associated with greater improvement in symptoms, with the mean difference between groups in the MAFSI frequency score favouring ablation over 5 years of follow-up in all subgroups: PAF had a clinically significant −1.9-point difference (95% CI: −1.2 to −2.6); PersAF a −0.9 difference (95% CI: −0.2 to −1.6); LSPAF a clinically significant difference of −1.6 points (95% CI: −0.1 to −3.1). Ablation was also associated with greater improvement in quality of life in all subgroups, with the AFEQT overall score in PAF patients showing a clinically significant 5.3-point improvement (95% CI: 3.3 to 7.3) over drug therapy alone over 5 years of follow-up, PersAF a 1.7-point difference (95% CI: 0.0 to 3.7), and LSPAF a 3.1-point difference (95% CI: -1.6 to 7.8). Conclusion Prognostic treatment effects of catheter ablation compared with drug therapy on the primary and major secondary clinical endpoints did not differ consequentially by AF subtype. With regard to decreases in AF recurrence and improving quality of life, ablation was more effective than drug therapy in all three AF type subgroups. ClinicalTrials.gov Identifier NCT00911508

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.

Background: The CABANA trial (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation) was a randomized, prospective trial of left atrial catheter ablation versus drug therapy for treatment of atrial fibrillation (AF). As part of CABANA, a prospective imaging substudy was conducted. The main objectives were to describe the patterns of changes in the dimensions of the left atrium and pulmonary veins (PVs), and the relationship between these changes with treatment assignment and clinical outcomes. Methods: Computed tomography or magnetic resonance imaging was acquired at baseline and follow-up in 121 ablation (median follow-up 101 days) and 85 drug patients (median follow-up 97 days). Left atrial volume index, mean PV ostial diameter, and ostial diameters of each PV separately were computed. We examined the relationship between the change from baseline to follow-up with subsequent clinical outcomes (composite of death, disabling stroke, serious bleeding, or cardiac arrest [CABANA primary end point], total mortality or cardiovascular hospitalization, first AF recurrence after the 90-day blanking period, first AF/atrial flutter/atrial tachycardia after the 90-day blanking period) using Cox proportional-hazards models. Results: The median (25th to 75th) change from baseline for left atrial volume index was −7.8 mL/m 2 (−16.4 to 0.2), ablation arm and −3.5 mL/m 2 (−11.4 to 2.6), drug therapy arm. The left atrial volume index decreased in 52.9% of ablation patients versus 40.0% of drug therapy patients. Change for mean PV was −2.7 mm (−4.2 to −1.3) in the ablation arm versus −0.1 mm (−1.5 to 0.8) in the drug therapy arm. Changes in left atrium and PV dimensions had no consistent relationship with the risk of developing the study primary end point. Reductions in left atrial volume index, and in mean PV diameter were associated with decreased risk of AF recurrence. Conclusions: Ablation patients demonstrated more frequent and larger atrial structural changes compared with drug patients. These changes suggest a critical relationship between structural features and AF generation.

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.

Abstract Background The CABANA trial compared drug vs ablation therapy yet did not identify a difference in the primary endpoint of death, stroke, severe bleeding, or cardiac arrest or the secondary endpoint of all-cause mortality by intention to treat (ITT) analysis. Nevertheless, there was evidence of improved outcomes and survival in the as-treated and per-protocol analyses. Objectives To determine how the treatment strategies of drug therapy vs ablation impact the atrial fibrillation progression and regression. Methods CABANA randomized 2204 pts with AF ≥65 yrs old or &lt;65 with ≥1 risk factor for stroke at 126 sites worldwide to ablation with pulmonary vein isolation vs drug including rate/rhythm control medication. AF type was recorded at the time of enrollment in the CABANA Trial. Following treatment with drug therapy or ablation, the AF type was assessed as recorded at the patient's last follow-up. Comparisons between baseline AF type and last AF type were performed according to ITT. Results Following treatment with ablation, 64% maintained sinus rhythm with elimination of AF, 11% experienced AF regression, and only 7% had progression of AF. In contrast, in those randomized to drug therapy, only 48% experienced maintenance of sinus rhythm, 10% experienced AF regression, and 13% had progression of AF. Moreover, in the drug arm there was a 32% increase in long-standing persistent compared with a 49% reduction in the ablation arm. Conclusion Catheter ablation significantly alters the natural history of atrial fibrillation. Intention to treat analysis reveals that catheter ablation provides superior elimination of AF, protection against AF progression, and dramatically lower risks of long-standing persistent AF. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health

Abstract Background Unexpected variations in treatment benefits by geographic region raise questions about the generalizability of findings from international clinical trials. Purpose Investigate the outcome of catheter ablation vs drug therapy in CABANA patients with AF treated at North American (NA) compared with non-NA sites, a pre-specified comparison. Methods CABANA randomized 2204 symptomatic patients with atrial fibrillation (AF) to ablation vs drug therapy at 126 centers in 10 countries. The primary endpoint was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Results There were 1285 patients enrolled at 85 NA sites, and 919 at 45 non-NA sites. At baseline, NA and non-NA patients differed significantly with regard to age, sex, BMI, CCS, CHA2DS2-VASc score, family history of AF, prior AF hospitalization, history of A Flutter, diabetes, NYHA class, and proportion with sleep apnea, heart disease, CAD, CHF, or EF &gt;35%. Four-year Kaplan-Meier event rates showed considerable differences in treatment effects between NA and non-NA patients (see Table). Ablation was associated with a 50% reduction in the primary endpoint in non-NA (HR 0.50, 95% CI 0.24 to 1.03) vs a 5% reduction in NA (HR 0.95, 95% CI 0.69 to 1.30) enrollees despite higher event rates in NA patients. The trend of favorable outcome with ablation at non-NA sites was maintained after adjustment for baseline covariates that differed between the non-NA (HR 0.51, 95% CI 0.24 to 1.04) and NA populations (HR 0.93, 95% CI 0.68 to 1.20). Conclusion We observed substantial geographic variation in clinical outcomes and treatment effects in the CABANA trial that suggests an important disconnection between overall event rates and treatment benefit from ablation in AF. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): NIH

Abstract Background Sex-specific outcomes may differ amongst patients receiving catheter ablation for atrial fibrillation (AF). Purpose Assess sex-specific outcomes in the patients randomized to catheter ablation or drug therapy in CABANA. Methods CABANA randomized 2204 pts with AF to catheter ablation or drug therapy (rate/rhythm-control). The outcomes of combined death, disabling stroke, severe bleeding, or cardiac arrest (intention to treat-ITT) or all-cause death were not different. But, ablation significantly improved combined death or CV hospitalization. This analysis compares clinical characteristics by sex and determines sex-specific hazard ratios based on a comparison of ablation vs drug therapy. Results Females were 37.3% of ablation and 37.0% of drug therapy patients. Females were older, more often white race, had less CAD, or sleep apnea, but had higher NYHA Class, higher CHA2DS2VASc, and more often had paroxysmal (v. persistent) AF, and prior AF hospitalization. (Table) HTN, CVA and diabetes were the same (Table). For the CABANA primary endpoint, an ITT comparison of ablation vs. drug therapy, showed a female hazard ratio (HR) of 1.14 (95% confidence interval (CI) 0.70–1.86), and a male HR of 0.74, (95% CI 0.52–1.06). For all-cause mortality, the female HR was 0.75 (95% CI 0.41–1.40) and male HR was 0.91 (95% CI 0.59–1.40) and for all-cause mortality or CV hospitalization, the female HR was 0.90 (95% CI 0.75–1.09) and male HR was 0.79 (95% CI 0.69–0.92). All interaction p values were non-significant. Recurrent AF (post 90-day blanking) was significantly reduced for both females and males: female HR 0.64 (95% CI 0.51–0.82), male HR 0.46 95% CI 0.39–0.56), p=0.035 Clinical Characteristics and Outcomes Baseline Characteristics Female (N=818) Male (N=1385) p-value Age: Median (Q1, Q3) 69 (65, 74) 66 (60, 71) <0.001 White 766 (93.9%) 1259 (91.0%) 0.015 CAD 92 (11.2%) 332 (24.0%) <0.001 NYHA ≥II 345 (42.4%) 433 (31.5%) <0.001 Sleep apnea 136 (16.6%) 372 (26.9%) <0.001 CHA2DS2-VASc: Median (Q1, Q3) 3 (3, 4) 2 (1, 3) <0.001 Paroxysmal AF 406 (49.6%) 540 (39.0%) <0.001 Persistent AF 412 (50.4%) 845 (61.0%) AF Hospitalization 353 (43.2%) 521 (37.7%) 0.011 Conclusion Significant sex-specific outcomes differences were not observed. Sex should not be used as a determining factor in selecting patients for AF therapy. Acknowledgement/Funding NIH, St Jude Medical Foundation and Corporation, Biosense Webster Inc., Medtronic Corporation, and Boston Scientific Corporation