Association of Amiodarone Use Prior to Orthotopic Heart Transplant with Post-Transplant Graft Dysfunction and All-Cause Mortality: A Systematic Review and Meta-Analysis.

BACKGROUND: There is conflicting data on the association between pre-orthotopic heart transplant (OHT) amiodarone use and post-OHT graft dysfunction (GD) leading to heterogeneity in clinical practice. METHODS: We performed a meta-analysis to evaluate whether pre-OHT amiodarone use was associated with meaningful increases in the incidence of GD, 30-day mortality, and 1-year mortality. Studies were identified by searching PubMed and the Cochrane Register of Clinical Trials. The Mantel-Haenszel method was used to calculate odds ratios (OR) and 95% confidence intervals (CI95) for each endpoint. RESULTS: 17 retrospective studies were identified that included 48,782 patients. 14 studies (n = 48,018) reported GD as an outcome. Pre-OHT amiodarone use was associated with increased odds of GD (OR 1.3, CI95 1.2-1.5, p < 0.001). 10 studies (n = 45,875) reported 30-day mortality based on amiodarone use. Pre-OHT amiodarone use was associated with increased odds of 30-day mortality (OR 1.4, CI95 1.2-1.5, p < 0.001). 5 studies (n = 41,404) reported 1-year mortality based on amiodarone use. Pre-OHT amiodarone use was associated with increased odds of 1-year mortality (OR 1.2, CI95 1.1-1.4, p < 0.001). The increase in absolute risk of GD, 30-day mortality, and 1-year mortality for patients with pre-OHT amiodarone use was 1.3%, 1.2%, and 1.4%, respectively. CONCLUSION: Pre-OHT amiodarone exposure was associated with increased odds of GD, 30-day mortality, and 1-year mortality. The increase in absolute risk for each endpoint was modest, and it is unclear to what extent, if any, pre-OHT amiodarone use should influence assessment of OHT candidacy.

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.

A systematic review and meta-analysis of all sham and placebo controlled trials for resistant hypertension.

INTRODUCTION: There is a lack of consensus regarding the best add on therapy for treatment of resistant hypertension (RH). This is likely secondary to a paucity of data on the comparative effectiveness of proposed therapies for RH. METHODS: Placebo-controlled and sham-controlled randomized clinical trials testing therapies for the treatment of RH were included in this meta-analysis. Therapies with two or more studies were included as subgroups in this meta-analysis. The primary outcomes being tested were 24-hr systolic blood pressure (SBP) and office SBP. RESULTS: Eight studies were identified that tested mineralocorticoid receptor antagonist (MRA) including 1,414 participants. The raw mean difference (RMD) between MRA and placebo control was statistically significant for 24-hour SBP (-10.56 mmHg; 95% confidence interval (CI) -12.82 to -8.30), 24-hour diastolic (DBP) (-5.48 mmHg; 95% CI -8.48 to -2.58), office SBP (-11.97 mmHg; 95% CI -16.41 to -7.54), and office DBP (-4.14 mmHg; 95% CI -5.62 to -2.65). Six studies were identified that tested renal denervation (RD) including 989 participants. The RMD between RD and sham control was not statistically significant for 24-hour SBP (-1.84 mmHg; 95% CI -3.92 to 0.24), 24-hour DBP (-0.66 mmHg; 95% CI -1.85 to 0.54), office SBP (-1.57 mmHg; 95% CI -6.04 to 2.89), and office DBP (-1.49 mmHg; 95% CI -3.52 to 0.55). Four studies were identified that tested endothelin receptor antagonists (ERA) including 1,193 participants. The raw mean difference (RMD) between ERA and placebo control was statistically significant for 24-hr systolic (SBP) (-7.02 mmHg; 95% CI -9.15 to -4.90, 24-hr diastolic (DBP) (-6.22 mmHg; 95% CI -7.61 to -4.82), office SBP (-5.84 mmHg; 95% CI -10.08 to -1.60), and office DBP (-3.73 mmHg; 95% CI -5.87 to -1.59). DISCUSSION: MRA lowers BP in patients with RH more than RD, which seems to have little to no effect in RH. ERAs lead to a statistically significant reduction in BP but the confidence in efficacy is limited due to the low number of studies and differences in trial population. Individual factors and their impact on treatment response in RH should be investigated in future research.

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.

Non-pharmacologic autonomic neuromodulation for treatment of heart failure: A systematic review and meta-analysis of randomized controlled trials.

Treatment strategies that modulate autonomic tone through interventional and device-based therapies have been studied as an adjunct to pharmacological treatment of heart failure with reduced ejection fraction (HFrEF). The main objective of this study was to perform a meta-analysis of randomized controlled trials which evaluated the efficacy of device-based autonomic modulation for treatment of HFrEF. All randomized-controlled trials testing autonomic neuromodulation device therapy in HFrEF were included in this trial-level analysis. Autonomic neuromodulation techniques included vagal nerve stimulation (VNS), baroreflex activation (BRA), spinal cord stimulator (SCS), and renal denervation (RD). The prespecified primary endpoints included mean change and 95% confidence intervals (CI) of left ventricular ejection fraction (LVEF), NT pro-B-type natriuretic peptide (NT-proBNP), and quality of life (QOL) measures including 6-minute hall walk distance (6-MHWD), and Minnesota Living with Heart Failure Questionnaire (MLHFQ). New York Heart Association (NYHA) functional class improvement was reported as odds ratios and 95% CI of improvement by at least 1 functional class. Eight studies were identified that included 1037 participants (2 VNS, 2 BRA, 1 SCS, and 3 RD trials). This included 6 open-label, 1 single-blind, and 1 sham-controlled, double-blind study. The mean age (±SD) was 61 (±9.3) years. The mean follow-up time was 7.9 months. Twenty percent of the total patients were female, and the mean BMI (±SD) was 29.86 (±4.12). Autonomic neuromodulation device therapy showed a statistically significant improvement in LVEF (4.02%; 95% CI 0.24,7.79), NT-proBNP (-219.80 pg/ml; 95% CI -386.56, -53.03), NYHA functional class (OR 2.32; 95% CI 1.76, 3.07), 6-MHWD (48.39 m; 95% CI 35.49, 61.30), and MLHFQ (-12.20; 95% CI -19.24, -5.16) compared to control. In patients with HFrEF, the use of autonomic neuromodulation device therapy is associated with improvement in LVEF, reduction in NT-proBNP, and improvement in patient-centered QOL outcomes in mostly small open-label trials. Large, double-blind, sham-controlled trials designed to detect differences in hard cardiovascular outcomes are needed before widespread use and adoption of autonomic neuromodulation device therapies in HFrEF.

Age-related changes in sleep-dependent novel word consolidation.

Learning new words is a vital, life-long process that benefits from memory consolidation during sleep in young adults. In aging populations, promoting vocabulary learning is an attractive strategy to improve quality of life and workplace longevity by improving the integration of new technology and the associated terminology. Decreases in sleep quality and quantity with aging may diminish sleep-dependent memory consolidation for word learning. Alternatively, given that older adults outperform young adults on vocabulary-based tasks, and that strength of memory encoding (how well older adults learn) predicts sleep-dependent memory consolidation, word learning may uniquely benefit from sleep in older adults. We assessed age-related changes in memory for novel English word-definition pairs recalled following intervals spent asleep and awake. While sleep was shown to fully preserve memory for word/definition pairs in young adults (N = 53, asleep = 32, awake = 21, 18-30 years), older adults (N = 45, asleep = 21, awake = 24, 58-75 years) forgot items equally over wake and sleep intervals but preserved the accuracy of typed responses better following sleep. However, this was modulated by the strength of encoded memories: the proportion of high strength items consolidated increased for older adults following sleep compared to wake. Older adults consolidated a lower proportion of medium strength items across both sleep and wake intervals compared to young adults. Our results contribute to growing evidence that encoding strength is crucially important to understand the expression of sleep-dependent benefits in older adults and assert the need for sufficiently sensitive performance metrics in aging research.