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.

In a population-based, cross-sectional study, we assessed age-and sex-specific changes in bone structure by QCT. Over life, the cross-sectional area of the vertebrae and proximal femur increased by ϳ15% in both sexes, whereas vBMD at these sites decreased by 39 -55% and 34 -46%, respectively, with greater decreases in women than in men.Introduction: The changes in bone structure and density with aging that lead to fragility fractures are still unclear. Materials and Methods: In an age-and sex-stratified population sample of 373 women and 323 men (age, 20 -97 years), we assessed bone geometry and volumetric BMD (vBMD) by QCT at the lumbar spine, femoral neck, distal radius, and distal tibia. Results: In young adulthood, men had 35-42% larger bone areas than women (p Ͻ 0.001), consistent with their larger body size. Bone area increased equally over life in both sexes by ϳ15% (p Ͻ 0.001) at central sites and by ϳ16% and slightly more in men at peripheral sites. Decreases in trabecular vBMD began before midlife and continued throughout life (p Ͻ 0.001), whereas cortical vBMD decreases began in midlife. Average decreases in trabecular vBMD were greater in women (Ϫ55%) than in men (Ϫ46%, p Ͻ 0.001) at central sites, but were similar (Ϫ24% and Ϫ26%, respectively) at peripheral sites. With aging, cortical area decreased slightly, and the cortex was displaced outwardly by periosteal and endocortical bone remodeling. Cortical vBMD decreased over life more in women (ϳ25%) than in men (ϳ18%, p Ͻ 0.001), consistent with menopausal-induced increases in bone turnover and bone porosity. Conclusions: Age-related changes in bone are complex. Some are beneficial to bone strength, such as periosteal apposition with outward cortical displacement. Others are deleterious, such as increased subendocortical resorption, increased cortical porosity, and, especially, large decreases in trabecular vBMD that may be the most important cause of increased skeletal fragility in the elderly. Our findings further suggest that the greater age-related decreases in trabecular and cortical vBMD and perhaps also their smaller bone size may explain, in large part, why fragility fractures are more common in elderly women than in elderly men.

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Using QCT, we made a longitudinal, population-based assessment of rates of bone loss over life at the distal radius, distal tibia, and lumbar spine. Cortical bone loss began in perimenopause in women and later in life in men. In contrast, trabecular bone loss began in young adulthood in both sexes.Introduction: Although conventional wisdom holds that bone loss begins at menopause in women and later in life in men, this has not been examined longitudinally in population-based studies using precise technology capable of distinguishing cortical and trabecular bone. Materials and Methods:In an age-and sex-stratified population sample (n ‫ס‬ 553), we measured volumetric BMD (vBMD) of trabecular and cortical bone by QCT annually for up to 3 yr at the distal radius (DR) and distal tibia (DT) (n ‫ס‬ 552) and trabecular vBMD at baseline and 3 yr at the lumbar spine (LS) (n ‫ס‬ 474). Results: Substantial cortical bone loss began in middle life in women but began mainly after age 75 in men. In contrast, substantial trabecular bone loss began in young adult women and men at all three skeletal sites and continued throughout life with acceleration during perimenopause in women. Women experienced 37% and men experienced 42% of their total lifetime trabecular bone loss before age 50 compared with 6% and 15%, respectively, for cortical bone. Median rates of change in trabecular bone (%/yr) were −0.40, −0.24, and −1.61 in young adult women and −0.38, −0.40, and −0.84 in young adult men at the DR, DT, and LS, respectively (all p < 0.001). The early trabecular bone loss did not consistently correlate with putative causal factors, except for a trend with IGF-related variables at DT in women. However, in postmenopausal women and, to a lesser extent, in older men, higher rates of cortical and trabecular bone loss were associated with lower levels of biologically-active sex steroids and with higher levels of follicle-stimulating hormone and bone turnover markers. Conclusions:The late onset of cortical bone loss is temporally associated with sex steroid deficiency. However, the early-onset, substantial trabecular bone loss in both sexes during sex steroid sufficiency is unexplained and indicates that current paradigms on the pathogenesis of osteoporosis are incomplete.

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Vertebral fractures are more strongly associated with specific bone density, structure, and strength parameters than with areal BMD, but all of these variables are correlated.Introduction: It is unclear whether the association of areal BMD (aBMD) with vertebral fracture risk depends on bone density per se, bone macro-or microstructure, overall bone strength, or spine load/bone strength ratios. Materials and Methods: From an age-stratified sample of Rochester, MN, women, we identified 40 with a clinically diagnosed vertebral fracture (confirmed semiquantitatively) caused by moderate trauma (cases; mean age, 78.6 ± 9.0 yr) and compared them with 40 controls with no osteoporotic fracture (mean age, 70.9 ± 6.8 yr). Lumbar spine volumetric BMD (vBMD) and geometry were assessed by central QCT, whereas microstructure was evaluated by high-resolution pQCT at the ultradistal radius. Vertebral failure load (∼strength) was estimated from voxel-based finite element models, and the factor-of-risk () was determined as the ratio of applied spine loads to failure load. Results: Spine loading (axial compressive force on L 3 ) was similar in vertebral fracture cases and controls (e.g., for 90°forward flexion, 2639 versus 2706 N; age-adjusted p ‫ס‬ 0.173). However, fracture cases had inferior values for most bone density and structure variables. Bone strength measures were also reduced, and the factor-of-risk was 35-37% greater (worse) among women with a vertebral fracture. By age-adjusted logistic regression, relative risks for the strongest fracture predictor in each of the five main variable categories were bone density (total lumbar spine vBMD: OR per SD change, 2.2; 95% CI, 1.1-4.3), bone geometry (vertebral apparent cortical thickness: OR, 2.1; 95% CI, 1.1-4.1), bone microstructure (none significant); bone strength ("cortical" [outer 2 mm] compressive strength: OR, 2.5; 95% CI, 1.3-4.8), and factor-of-risk ( for 90°forward flexion/overall vertebral compressive strength: OR, 3.2; 95% CI, 1.4-7.5). These variables were correlated with spine aBMD (partial r, −0.32 to 0.75), but each was a stronger predictor of fracture in the logistic regression analyses. Conclusions:The association of aBMD with vertebral fracture risk is explained by its correlation with more specific bone density, structure, and strength parameters. These may allow deeper insights into fracture pathogenesis.

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