Mark, Daniel B.

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: Randomized clinical trials have demonstrated that catheter ablation for atrial fibrillation in patients with heart failure with reduced ejection fraction may improve survival and other cardiovascular outcomes. Methods: We constructed a decision-analytic Markov model to estimate the costs and benefits of catheter ablation and medical management in patients with symptomatic heart failure with reduced ejection fraction (left ventricular ejection fraction ≤35%) and atrial fibrillation over a lifetime horizon. Evidence from the published literature informed the model inputs, including clinical effectiveness data from meta-analyses. Probabilistic and deterministic sensitivity analyses were performed. A 3% discount rate was applied to both future costs and benefits. The primary outcome was the incremental cost-effectiveness ratio assessed from the US health care sector perspective. Results: Catheter ablation was associated with 6.47 (95% CI, 5.89–6.93) quality-adjusted life years (QALYs) and a total cost of $105 657 (95% CI, $55 311–$191 934; 2018 US dollars), compared with 5.30 (95% CI, 5.20–5.39) QALYs and $63 040 (95% CI, $37 624–$102 260) for medical management. The incremental cost-effectiveness ratio for catheter ablation compared with medical management was $38 496 (95% CI, $5583–$117 510) per QALY gained. Model inputs with the greatest variation on incremental cost-effectiveness ratio estimates were the cost of ablation and the effect of catheter ablation on mortality reduction. When assuming a more conservative estimate of the treatment effect of catheter ablation on mortality (hazard ratio of 0.86), the estimated incremental cost-effectiveness ratio was $74 403 per QALY gained. At a willingness-to-pay threshold of $100 000 per QALY gained, atrial fibrillation ablation was found to be economically favorable compared with medical management in 95% of simulations. Conclusions: Catheter ablation in patients with heart failure with reduced ejection fraction patients and atrial fibrillation may be considered economically attractive at current benchmarks for societal willingness-to-pay in the United States.

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

Background: Inconclusive noninvasive tests complicate the care of patients with suspected coronary artery disease, but their prevalence and impact on management, outcomes, and costs are not well described. Methods: PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) patients were randomized to stress testing (n=4533) or computed tomographic angiography (CTA; n=4677). We assessed relationships between inconclusive results, subsequent testing, a composite outcome (death, myocardial infarction, or hospitalization for unstable angina), and healthcare expenditures. Results: Overall, 8.0% of tests were inconclusive (9.7% stress, 6.4% CTA). Compared with negative tests, inconclusive tests were more often referred to a second noninvasive test (stress: 14.6% versus 8.5%, odds ratio [OR], 1.91; CTA: 36.5% versus 8.4%, OR, 5.95; P <0.001) and catheterization (stress: 5.5% versus 2.4%, OR, 2.36; CTA: 23.4% versus 4.1%, OR, 6.49; P <0.001), and composite outcomes were higher for both inconclusive tests (stress: 3.7% versus 2.0%, hazard ratio, 1.81, P =0.034; CTA: 5.0% versus 2.2%, hazard ratio, 1.85; P =0.044) and positive tests (stress: 8.3% versus 2.0%, hazard ratio, 3.50; CTA: 9.2% versus 2.2%, hazard ratio, 3.66; P <0.001). Twenty-four–month costs were higher for inconclusive tests than negative tests by $2905 (stress) and $4030 (CTA). Conclusions: Among patients with stable chest pain undergoing a noninvasive test, inconclusive results occurred in 6% of CTA and 10% of stress tests. Compared with those with conclusive negative tests, individuals with inconclusive results more often underwent subsequent testing, had increased medical costs, and experienced worse outcomes. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01174550.

Background: The optimal timing of catheter ablation for atrial fibrillation (AF) in reference to the time of diagnosis is unknown. We sought to assess the impact of the duration between first diagnosis of AF and ablation, or diagnosis-to-ablation time (DAT), on AF recurrence following catheter ablation. Methods: We conducted a systematic electronic search for observational studies reporting the outcomes associated with catheter ablation for atrial fibrillation stratified by diagnosis-to-ablation time. The primary meta-analysis using a random effects model assessed AF recurrence stratified by DAT ≤1 year versus >1 year. A secondary analysis assessed outcomes stratified by DAT ≤3 years versus >3 years. Results: Of the 632 screened studies, 6 studies met inclusion criteria for a total of 4950 participants undergoing AF ablation for symptomatic AF. A shorter DAT ≤1 year was associated with a lower relative risk of AF recurrence compared with DAT >1 year (relative risk, 0.73 [95% CI, 0.65–0.82]; P <0.001). Heterogeneity was moderate (I 2 =51%). When excluding the one study consisting of only patients with persistent AF, the heterogeneity improved substantially (I 2 =0%, Cochran’s Q P =0.55) with a similar estimate of effect (relative risk, 0.78 [95% CI, 0.71–0.85]; P <0.001). Conclusions: Shorter duration between time of first AF diagnosis and AF ablation is associated with an increased likelihood of ablation procedural success. Additional study is required to confirm these results and to explore implementation of earlier catheter AF ablation and patient outcomes within the current AF care pathway. Visual Overview A visual overview is available for this article.

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

Abstract Background Prior studies suggest that catheter ablation (ABL) for atrial fibrillation (AF) is a treatment option for patients (pts) with paroxysmal AF (PAF). Pts with persistent (Per) or long-standing persistent (LSP) were routinely excluded from most ABL based clinical trials. The effectiveness of ABL compared to drug therapy (MED) in relation to underlying AF type has not been evaluated in a large randomized clinical trial. Objective To assess the impact of AF type on clinical outcomes of ABL vs. MED in pts with AF. Methods The CABANA trial randomized 2204 pts with AF at 126 sites worldwide to ABL vs. MED with rate or rhythm control drugs. The primary endpoint was a composite of death, disabling stroke, severe bleeding, or cardiac arrest. Key secondary endpoints included mortality and recurrence of AF. Outcomes of ABL vs. MED were compared within subgroups defined by AF type using Intention-to-Treat (ITT) analyses. Results Of the 2204 pts, 946 had PAF, 1042 had Per and 215 presented with LSP. There were baseline differences among AF types in age, gender, HTN, LVH, CHF and NYHA Class. For the primary endpoint, there were no significant differences between ABL and MED in pts with PAF (hazard ratio (HR) 0.82; 95% confidence interval (CI) 0.51, 1.31), Per (HR 0.87; 95% CI 0.59, 1.28), or LSP (HR 1.01, 95% CI 0.39, 2.61). Likewise, there were no significant treatment differences in mortality; PAF (HR 0.84; 95% CI 0.46, 1.52), Per (HR 0.90; 95% CI 0.56, 1.46) and LSP (HR 0.67, 95% CI 0.23, 1.94). Post-blanking AF (time to first recurrence) was significantly reduced by ABL compared to MED across all AF types (PAF by 51%), (Per by 47%) and (LSP by 36%). Clinical Characteristics and Outcomes Clinical Outcomes Comparing ABL vs. MED (HR and 95% CI) Interaction p-value Primary Endpoint 0.82 (0.51, 1.31) 0.87 (0.59, 1.28) 1.01 (0.39, 2.61) 0.925 Mortality 0.84 (0.46, 1.52) 0.90 (0.56, 1.46) 0.67 (0.23, 1.94) 0.881 Recurrent AF 0.49 (0.38, 0.62) 0.53 (0.43, 0.65) 0.64 (0.41, 1.01) 0.564 Conclusion Pts with LSP have a lower proportion of women, and a higher proportion with manifestations of heart failure despite lower CHA2DS2VASc scores. By ITT analysis, there is no significant effect of ABL compared to MED in the primary endpoint or mortality in any AF group. However, ABL is more effective than MED for reducing recurrences of AF regardless of AF type, but with a greater effect in PAF vs Per vs LSP. Acknowledgement/Funding NIH, St Jude Medical Foundation and Corporation, Biosense Webster Inc., Medtronic Corporation, and Boston Scientific Corporation

Objectives To test the relationship between increasing severity of obesity, calculated risk and observed outcomes. Methods Patients with symptoms suggestive of coronary artery disease (CAD) (n=10 003) were stratified according to body mass index (BMI). We compared risk factors, pooled risk scores and physicians’ perception of risk. Cox regression tested the association between BMI and (1) presence of obstructive CAD and (2) composite clinical endpoints (death, cardiovascular death, unstable angina hospitalisation and myocardial infarction). Results BMI was ≥30 kg/m2 in 48% of patients and ≥35 in 20%. Increasingly obese patients were younger, female and non-smoking but with higher prevalence of hypertension, diabetes, black race and sedentary lifestyle. Pooled risk estimates of CAD were highest in those with mid-range BMI. In contrast, physicians’ estimation of the likelihood of significant CAD based on clinical impression increased progressively with BMI. For a 10% increase in the Diamond-Forrester probability of CAD, the adjusted OR for obstructive CAD was 1.5 (95% CI 1.4 to 1.5) in patients with BMI <35, but only 1.2 (95% CI 1.1 to 1.3) in those with BMI ≥35 (interaction p<0.001). Framingham Risk Score increased across increasing BMI categories. However, there was a strong and consistent inverse relationship between degree of obesity and all three composite clinical endpoints over a median 25 months of follow-up. Conclusions Despite perceptions of higher risk and higher risk scores, increasingly obese patients had obstructive CAD less frequently than predicted and had fewer adverse clinical outcomes. There is a need for risk assessment tools and guidelines that account for obesity. Trial registration number NCT01174550.