Obese patients with new onset atrial fibrillation/flutter have higher risk of hospitalization, cardioversions, and ablations.

Obesity significantly increases the risk of developing atrial fibrillation (AF) and atrial flutter (AFL) and evidence from randomized trials indicates that weight loss may reduce the burden of AF/AFL in obese patients; however, the relationship between obesity and healthcare resource utilization in AF/AFL patients is lacking. We sought to assess this relationship in patients with newly diagnosed AF/AFL in a nationally representative cohort of the United States by using the MarketScan® claims database. International Classification of Diseases, Tenth Revision [ICD 10] diagnosis codes were used to select individuals with a new diagnosis of AF/AFL in 2017 and 2018, adjudicate baseline variables and to classify them according to obesity status. Patients were followed for two years at which point all data was censored. The primary outcome of the study was hospitalizations due to AF/AFL. Cox proportional hazards regression models were used to assess the adjusted hazard ratio for obese versus non-obese patients. There were 55,271 patients with new onset AF/AFL, which included 43,314 (78.4 %) who were non-obese and 11,957 (21.6 %) who were obese. There were significantly more males than females among non-obese (65.3 % vs. 34.7 %) and obese individuals (62.3 % vs. 37.7 %). The average age (SD) was similar in the non-obese (54.5 (9.7)) and obese cohorts (54.7 (8.4)), respectively. The incidence of Emergency Department visits (4.0 % vs. 6.5 %), hospitalizations (5.5 % vs. 10.7 %), cardioversions (6.6 % vs. 12.7 %), and ablation procedures (5.3 % vs. 8.6 %) were significantly increased among obese patients.

Re-Analyses of 8 Historical Trials in Cardiovascular Medicine Assessing Multimorbidity Burden and Its Association with Treatment Response.

OBJECTIVE: The purpose of this study was to examine the multimorbidity burden of clinical trial participants and assess its association with treatment response. METHODS: We conducted a reanalysis of patient level data. There were 29,954 participants from 8 clinical trials containing 11 comparisons between an intervention and control condition. Patients were classified by Charlson Comorbidity Index (CCI) score. The primary outcomes were the primary study endpoints as originally specified for each trial. A Cox model that included the CCI score groups, the randomized group, and their interaction, was used to compare the primary outcome between randomized groups. The interaction term between randomized group and comorbidity index allowed the treatment effect to differ by level of comorbidity index and comprised the primary effect of interest. Hazard ratios and risk differences were reported for all comparisons. RESULTS: The mean CCI scores of trial populations ranged from 2.1 to 3.9 points, and the percentage of patients with scores ≥5 from 3% to 39%. Tests of interaction terms in models yielded P values ≤ .10 for 4/11 comparisons and ≤ .05 for 2/11 comparisons. In 3 additional comparisons, potentially important treatment variation on an absolute scale was observed despite interaction tests with P values > .10 on the relative scale. CONCLUSIONS: These trials were mainly composed of patient populations with CCI scores ≤4. Despite this, biologically plausible treatment interactions were commonly suggested. These results are hypothesis generating; confirmation of results would require larger studies or studies targeted specifically toward patients with higher levels of multimorbidity.

Pulmonary vein isolation plus adjunctive therapy for the treatment of atrial fibrillation: a systematic review and meta-analysis.

BACKGROUND: Pulmonary vein isolation (PVI) is the primary technique for ablation of atrial fibrillation (AF). It is unclear whether adjunctive therapies in addition to PVI can reduce atrial arrhythmia recurrence (AAR) compared to PVI alone in patients with AF. METHODS: A meta-analysis of randomized controlled trials comparing PVI plus an adjunctive therapy (autonomic modulation, linear ablation, non-pulmonary vein trigger ablation, epicardial PVI [hybrid ablation], or left atrial substrate modification) to PVI alone was conducted. The primary outcome was AAR. Cumulative odd's ratios (OR) and 95% confidence intervals (CI) were calculated for each treatment type. RESULTS: Forty-six trials were identified that included 8,500 participants. The mean age (± standard deviation) was 60.2 (±4.1) years, and 27.2% of all patients were female. The mean follow-up time was 14.6 months. PVI plus autonomic modulation and PVI plus hybrid ablation were associated with a relative 53.1% (OR 0.47; 95% CI 0.32 to 0.69; p < 0.001) and 59.1% (OR 0.41; 95% CI 0.23 to 0.75; p = 0.003) reduction in AAR, respectively, compared to PVI alone. All categories had at least moderate interstudy heterogeneity except for hybrid ablation. CONCLUSION: Adjunctive autonomic modulation and epicardial PVI may improve the effectiveness of PVI. Larger, multi-center randomized controlled trials are needed to evaluate the efficacy of these therapies.

Controversies in Hypertension V: Resistant and Refractory Hypertension.

Apparent resistant hypertension, defined as uncontrolled office blood pressure despite ≥ 3 antihypertensive medications including a diuretic or use of ≥ 4 medications regardless of blood pressure, occurs in ≤ 15% of treated hypertensives. Apparent refractory hypertension, defined as uncontrolled office pressure despite use of 5 or more medications including a diuretic, occurs in ≤ 10% of resistant cases. Both are associated with increased comorbidity and enhanced cardiovascular risk. To rule out pseudo-resistant or pseudo-refractory hypertension, employ guideline-based methodology for obtaining pressure, maximize the regimen, rule out white-coat effect, and assess adherence. True resistant hypertension is characterized by volume overload and aldosterone excess, refractory by enhanced sympathetic tone. Spironolactone is the preferred agent for resistance, with lower doses. Spironolactone, potassium binders, or both, are preferred if the estimated glomerular filtration rate is below 45. If significant albuminuria, finerenone is indicated. The optimal treatment of refractory hypertension is unclear, but sympathetic inhibition (α-ß blockade, centrally acting sympathoinhibitors, or both) seems reasonable. Renal denervation has shown minimal benefit for resistance, but its role in refractory hypertension remains to be defined.

Controversies in Hypertension IV: Renal Denervation.

Renal denervation is not a cure for hypertension. Although more recent sham-controlled trials were positive, a significant minority of patients in each trial were unresponsive. The optimal patient or patients need to be defined. Combined systolic/diastolic hypertension appears more responsive than isolated systolic hypertension. It remains uncertain whether patients with comorbidities associated with higher adrenergic tone should be targeted, including obesity, diabetes, sleep apnea, and chronic kidney disease. No biomarker can adequately predict response. A key to a successful response is the adequacy of denervation, which currently cannot be assessed in real time. It is uncertain what is the optimal denervation methodology: radiofrequency, ultrasound, or ethanol injection. Radiofrequency requires targeting the distal main renal artery plus major branches and accessory arteries. Although denervation appears to be safe, conclusive data on quality of life, improved target organ damage, and reduced cardiovascular events/mortality are required before denervation can be generally recommended.

Controversies in Hypertension III: Dipping, Nocturnal Hypertension, and the Morning Surge.

A comprehensive approach to hypertension requires out-of-office determinations by home or ambulatory monitoring. The 4 phenotypes comparing office and out-of-office pressures in treated and untreated patients include normotension, hypertension, white-coat phenomena, and masked phenomena. Components of out-of-office pressure may be equally as important as mean values. Nighttime pressures are normally 10%-20% lower than daytime (normal "dipping") pressures. Abnormalities include dipping more than 20% (extreme dippers), less than 10 % (nondippers), or rising above daytime (risers) and have been associated with elevated cardiovascular risk. Nighttime pressure may be elevated (nocturnal hypertension) in isolation or together with daytime hypertension. Isolated nocturnal hypertension theoretically changes white-coat hypertension to true hypertension and normotension to masked hypertension. Pressure normally peaks in the morning hours ("morning surge") when cardiovascular events are most common. Morning hypertension may result from residual nocturnal hypertension or an exaggerated surge and has been associated with enhanced cardiovascular risk, especially in Asian populations. Randomized trials are needed to determine whether altering therapy based solely on either abnormal dipping, isolated nocturnal hypertension, or an abnormal surge is justified.

Effect of dronedarone vs. placebo on atrial fibrillation progression: a post hoc analysis from ATHENA trial.

AIMS: This post hoc analysis of the ATHENA trial (NCT00174785) assessed the effect of dronedarone on the estimated burden of atrial fibrillation (AF)/atrial flutter (AFL) progression to presumed permanent AF/AFL, and regression to sinus rhythm (SR), compared with placebo. METHODS AND RESULTS: The burden of AF/AFL was estimated by a modified Rosendaal method using available electrocardiograms (ECG). Cumulative incidence of permanent AF/AFL (defined as ≥6 months of AF/AFL until end of study) or permanent SR (defined as ≥6 months of SR until end of study) were calculated using Kaplan-Meier estimates. A log-rank test was used to assess statistical significance. Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were estimated using a Cox model, adjusted for treatment group. Of the 4439 patients included in this analysis, 2208 received dronedarone, and 2231 placebo. Baseline and clinical characteristics were well balanced between groups. Overall, 304 (13.8%) dronedarone-treated patients progressed to permanent AF/AFL compared with 455 (20.4%) treated with placebo (P < 0.0001). Compared with those receiving placebo, patients receiving dronedarone had a lower cumulative incidence of permanent AF/AFL (log-rank P < 0.001; HR: 0.65; 95% CI: 0.56-0.75), a higher cumulative incidence of permanent SR (log-rank P < 0.001; HR: 1.19; 95% CI: 1.09-1.29), and a lower estimated AF/AFL burden over time (P < 0.01 from Day 14 to Month 21). CONCLUSION: These results suggest that dronedarone could be a useful antiarrhythmic drug for early rhythm control due to less AF/AFL progression and more regression to SR vs. placebo, potentially reflecting reverse remodeling. CLINICAL TRIAL REGISTRATION: NCT00174785.

A Subgroup Meta-Analysis Comparing the Renal Denervation Sham-Controlled Randomized Trials Among Those With Resistant and Nonresistant Hypertension.

Renal denervation (RD) has been investigated as an invasive blood pressure (BP) lowering treatment for hypertension (HTN). Resistant HTN (RHTN) has been defined as uncontrolled BP despite use of 3 antihypertensive medications of different classes, including a diuretic, at maximum tolerated doses. The impact of RD on RHTN remains under investigation. Ten sham-controlled trials testing RD were included in this trial-level analysis. A prespecified subgroup analysis was conducted to test whether efficacy of RD differed in patients with and without RHTN. The primary end points were change in 24-hour ambulatory systolic (SBP) and diastolic (DBP) using raw mean difference (RMD) between sham control and RD. Ten studies (6 RHTN and 4 nonresistant HTN) were identified that included 1,544 participants (1,001 RHTN and 543 essential HTN) with cumulative mean age (±SD) of 57 years (±3). Cochran risk of bias assessment showed 69% of the domains to be at low risk of bias. The RMD for 24-hour SBP between RD and sham control was statistically significant for nonresistant HTN trials (-4.19 mm Hg; 95% confidence interval [CI] -6.07 to -2.30) but was not statistically significant for RHTN trials (-1.86 mm Hg; 95% CI - 3.89 to 0.16). Despite the numerical difference in the subgroups, the interaction between subgroups failed to reach statistical significance (p = 0.10). The RMD for 24-hour DBP between RD and sham control was statistically significant for nonresistant HTN trials (-2.60 mm Hg; 95% CI -3.79 to -1.42) but was not statistically significant for RHTN trials (-0.67 mm Hg; 95% CI -1.84 to 0.50). The interaction between subgroups was statistically significant (p = 0.02). Our analysis indicates RD is a less effective intervention for patients with RHTN. These data may be beneficial for clinicians to consider when assessing patients with RHTN for RD.

A systematic review, meta-analysis, and meta regression of the sham controlled renal denervation randomized controlled trials.

Renal denervation (RD) has been investigated as a novel blood pressure (BP) lowering treatment for hypertension. The primary objective of this meta-analysis was to assess the efficacy of RD and factors that may associate with treatment effect heterogeneity. The primary outcomes were raw mean differences (RMD) in 24-hour ambulatory, daytime ambulatory, nighttime, and office systolic BP (SBP) and diastolic BP (DBP) between sham control and RD. A prespecified subgroup analysis was performed comparing studies with follow-up less than versus greater than 4 months. If inter-study heterogeneity was found for any of the above outcomes, additional analyses were performed to assess potential moderator variables. Ten sham-controlled randomized trials were identified and included 1,544 participants, followed for a mean of 4.20 months. RD was associated with a statistically significant reduction in all SBP and DBP measures except for nighttime SBP (-2.64 mmHg; 95% confidence interval (CI) -5.84 to 0.56, p = 0.11) and nighttime DBP (- 1.21 mmHg; 95% CI -3.17 to 0.75, p = 0.23). Mild to moderate inter-study heterogeneity was identified for three outcomes (office SBP and nighttime SBP and DBP). Studies that followed patients for longer than 4 months had numerically lower reductions in most BP outcomes; however, there were no statistically significant interactions between subgroups. Compared to a sham procedure, RD was associated with statistically significant reductions in most measures of SBP and DBP that were within bounds of what would be expected from standard blood pressure lowering medications.