Al‐Khalidi, Hussein R.

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 <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 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

Background The impact of diabetes mellitus on the clinical presentation and noninvasive test ( NIT ) results among stable outpatients presenting with symptoms suggestive of coronary artery disease ( CAD ) has not been well described. Methods and Results The PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial enrolled 10 003 patients with known diabetic status, of whom 8966 were tested as randomized and had interpretable NIT results (1908 with diabetes mellitus, 21%). Differences in symptoms and NIT results were evaluated using logistic regression. Patients with diabetes mellitus (versus without) were similar in age (median 61 versus 60 years) and sex (female 54% versus 52%), had a greater burden of cardiovascular comorbidities, and had a similar likelihood of nonchest pain symptoms (29% versus 27%). The Diamond‐Forrester/Coronary Artery Surgery Study score predicted that patients with diabetes mellitus (versus without) had similar likelihood of obstructive CAD (low 1.8% versus 2.7%; intermediate 92.3% versus 92.6%; high 5.9% versus 4.7%). Physicians estimated patients with diabetes mellitus to have a higher likelihood of obstructive CAD (low to very low: 28.3% versus 40.1%; intermediate 63.9% versus 55.9%; high to very high 7.8% versus 4.0%). Patients with diabetes mellitus (versus without) were more likely to have a positive NIT result (15% versus 11%; adjusted odds ratio, 1.23; P =0.01). Conclusions Stable chest pain patients with and without diabetes mellitus have similar presentation and pretest likelihood of obstructive CAD ; however, physicians perceive that patients with diabetes mellitus have a higher pretest likelihood of obstructive CAD , an assessment supported by increased risk of a positive NIT . Further evaluation of diabetes mellitus's influence on CAD assessment is required. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 01174550.

Background Prior studies have demonstrated a link between the metabolic syndrome and increased risk of cardiovascular mortality. Whether the metabolic syndrome is associated with sudden cardiac death is uncertain. Methods and Results We characterized the relationship between sudden cardiac death and metabolic syndrome status among participants of the ARIC (Atherosclerosis Risk in Communities) Study (1987–2012) free of prevalent coronary heart disease or heart failure. Among 13 168 participants, 357 (2.7%) sudden cardiac deaths occurred during a median follow‐up of 23.6 years. Participants with the metabolic syndrome (n=4444) had a higher cumulative incidence of sudden cardiac death than those without it (n=8724) (4.1% versus 2.3%, P <0.001). After adjustment for participant demographics and clinical factors other than components of the metabolic syndrome, the metabolic syndrome was independently associated with sudden cardiac death (hazard ratio, 1.70, 95% confidence interval, 1.37–2.12, P <0.001). This relationship was not modified by sex (interaction P =0.10) or race (interaction P =0.62) and was mediated by the metabolic syndrome criteria components. The risk of sudden cardiac death varied according to the number of metabolic syndrome components (hazard ratio 1.31 per additional component of the metabolic syndrome, 95% confidence interval, 1.19–1.44, P <0.001). Of the 5 components, elevated blood pressure, impaired fasting glucose, and low high‐density lipoprotein were independently associated with sudden cardiac death. Conclusions We observed that the metabolic syndrome was associated with a significantly increased risk of sudden cardiac death irrespective of sex or race. The risk of sudden cardiac death was proportional to the number of metabolic syndrome components.

Objectives To define the prognostic contribution of global and regional left ventricular (LV) function measurements in patients with ischaemic cardiomyopathy randomised to coronary artery bypass graft surgery (CABG) with (n=501) or without (n=499) surgical ventricular reconstruction (SVR). Methods Novel multivariable methods to analyse global and regional LV systolic function were used to better formulate prediction models for long-term mortality following CABG with or without SVR in the entire cohort of 1000 randomised SVR hypothesis patients. Key clinical variables were included in the analysis. Regional function was classified according to the discreteness of anteroapical hypokinesia and akinesia into those most likely to benefit from SVR, those least likely and those felt to have intermediate likelihood of benefit from SVR. Results The most prognostic clinical variables identified in multivariable models include creatinine, LV end-systolic volume index (ESVI), age and NYHA (New York Heart Association) class. Addition of LV ejection fraction, LV end-diastolic volume index and regional function assessment did not contribute additional power to the model. Subgroup analysis based on regional function did not identify a cohort in which SVR improved mortality. Conclusions ESVI is the single parameter of LV function most predictive of mortality in patients with LV systolic dysfunction following CABG with or without SVR in multivariable models that include all key clinical and LV systolic function parameters. Assessment of regional cardiac function does not enhance prediction of mortality nor identify a subgroup for which SVR improves mortality. These results do not support elective addition of LV reconstruction surgery in patients undergoing CABG. Trial registration number NCT00023595.

Background— Racial and ethnic minorities are under-represented in clinical trials of primary prevention implantable cardioverter-defibrillators (ICDs). This analysis investigates the association between primary prevention ICDs and mortality among Medicare, racial/ethnic minority patients. Methods and Results— Data from Get With The Guidelines-Heart Failure Registry and National Cardiovascular Data Registry’s ICD Registry were used to perform an adjusted comparative effectiveness analysis of primary prevention ICDs in Medicare, racial/ethnic minority patients (nonwhite race or Hispanic ethnicity). Mortality data were obtained from the Medicare denominator file. The relationship of ICD with survival was compared between minority and white non-Hispanic patients. Our analysis included 852 minority patients, 426 ICD and 426 matched non-ICD patients, and 2070 white non-Hispanic patients (1035 ICD and 1035 matched non-ICD patients). Median follow-up was 3.1 years. Median age was 73 years, and median ejection fraction was 23%. Adjusted 3-year mortality rates for minority ICD and non-ICD patients were 44.9% (95% confidence interval [CI], 44.2%–45.7%) and 54.3% (95% CI, 53.4%–55.1%), respectively (adjusted hazard ratio, 0.79; 95% CI, 0.63–0.98; P =0.034). White non-Hispanic patients receiving an ICD had lower adjusted 3-year mortality rates of 47.8% (95% CI, 47.3%–48.3%) compared with 57.3% (95% CI, 56.8%–57.9%) for those with no ICD (adjusted hazard ratio, 0.75; 95% CI, 0.67%–0.83%; P <0.0001). There was no significant interaction between race/ethnicity and lower mortality risk with ICD ( P =0.70). Conclusions— Primary prevention ICDs are associated with lower mortality in nonwhite and Hispanic patients, similar to that seen in white, non-Hispanic patients. These data support a similar approach to ICD patient selection, regardless of race or ethnicity.