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OBJECTIVETo determine the effects of intensive systolic blood pressure (SBP) lowering on the risk of major adverse kidney outcomes in people with type 2 diabetes mellitus (T2DM) and/or prediabetes and cardiovascular risk factors.RESEARCH DESIGN AND METHODSThis post hoc ACCORD-BP subgroup analysis included participants in the standard glucose-lowering arm with cardiovascular risk factors required for SPRINT eligibility. Cox proportional hazards regression models compared the hazard for the composite of dialysis, kidney transplant, sustained estimated glomerular filtration rate (eGFR) 3.3 mg/dL, or a sustained eGFR decline ≥57% between the intensive (RESULTSThe study cohort included 1,966 SPRINT-eligible ACCORD-BP participants (40% women) with a mean age of 63 years. The mean SBP achieved after randomization was 120 ± 14 and 134 ± 15 mmHg in the intensive and standard arms, respectively. The kidney composite outcome occurred at a rate of 9.5 and 7.2 events per 1,000 person-years in the intensive and standard BP arms (hazard ratio [HR] 1.35 [95% CI 0.85–2.14]; P = 0.20). Intensive SBP lowering did not affect the risk of moderately (HR 0.96 [95% CI 0.76–1.20]) or severely (HR 0.92 [95% CI 0.66–1.28]) increased albuminuria. Including SPRINT participants with prediabetes in the cohort did not change the overall results.CONCLUSIONSThis post hoc subgroup analysis suggests that intensive SBP lowering does not increase the risk of major adverse kidney events in individuals with T2DM and cardiovascular risk factors.

Purpose: Malignancy after heart transplantation is associated with poor outcomes. At present, no prediction model exists for any malignancy within the first year after transplant. Methods: We studied adults who underwent heart transplantation included in the multicenter, national Scientific Registry of Transplant Recipients from January 2000 through April 2021. Possible predictors of malignancy were identified based on their known association with malignancy. Multiple imputations were conducted for missing values using predictive mean matching. A multivariable logistic regression model for predicting malignancy development within the first year after transplant was developed and internally validated via 500 bootstrapped samples to estimate the optimism-corrected measures of model accuracy and performance. Results: Among the 47 212 recipients comprising 16% females, 76% whites, 7% with prior malignancy, and a median age of 56 years; 865 (2.3% of those with non-missing data) developed malignancy within the first year after transplant. Prior malignancy, older age at heart transplantation, white race, and nonischemic heart failure etiology were the strongest predictors of new malignancy. The optimism-corrected model had modest discrimination (C-statistic: 0.70, 95% CI: 0.69-0.72) and good calibration and performance (calibration slope: 0.96; Cox-Snell R2: 0.063), particularly at lower predicted risk. A nomogram for the practicing clinician was developed. Conclusions: Using selection variables previously linked to cutaneous malignancy, our model was modestly predictive of the development of any malignancy in the first year after heart transplantation. Future research could identify factors that may improve malignancy prediction, including incorporation of time-to-event data.

With the implementation of the new heart transplant (HT) allocation system, patients requiring biventricular support systems have the highest priority, a shorter waitlist time, and a higher frequency of HT. However, the short-term and long-term outcomes of such patients are often disputed. Hence, we examined the outcomes of these patients who underwent HT before change in allocation scheme. Additionally, we compared post-HT outcomes of extracorporeal membrane oxygenation (ECMO) with other nondischargeable biventricular (BiVAD) supported patients. We identified adult ECMO or BiVAD supported HT recipients between 2000 and 2018 in the Scientific Registry of Transplant Recipients database. We compared survival with the Kaplan-Meier method. Using overlap propensity score weighting, we constructed Cox proportional hazards regression models to determine the risk-adjusted influence of BiVAD versus ECMO on survival. Of the 730 patients HT recipients; 528 (72.3%) and 202 (27.7%) were bridged with BiVAD and ECMO, respectively. For BiVAD versus ECMO patients, the 30-day, 1-year, 3-year, and 5-year mortality rates were 8.0% versus 14.4%, 16.3% versus 21.3%, 22.4% versus 25.3%, and 26.3% versus 25.7%, respectively. Risk-adjusted post-HT survival of BiVAD and ECMO patients at 30-day (HR 1.24 [95% CI, 0.68-2.27]; P = 0.4863), 1-year (HR 1.29 [95% CI, 0.80-2.09]; P = 0.3009), 3-year (HR 1.27 [95% CI, 0.83-1.94]; P = 0.2801), and 5-year (HR 1.35, 95% CI, 0.90-2.05; P = 0.1501) were similar. Around three-fourth of the ECMO or BiVAD supported patients were alive at 5-years post-HT. The short-term and long-term post-HT survivals of groups were comparable.

Objective: To determine the effects of intensive systolic blood pressure (SBP) lowering on the risk of major adverse kidney outcomes in people with type 2 diabetes mellitus (T2DM) and/or prediabetes and cardiovascular risk factors. Research Design and Methods: This post-hoc ACCORD-BP subgroup analysis included participants in the standard glucose-lowering arm with cardiovascular risk factors required for SPRINT eligibility. Cox proportional hazards regression models compared the hazard for the composite of dialysis, kidney transplant, sustained eGFR 3·3 mg/dL, or a sustained eGFR decline ≥57%, between the intensive ( Results: The study cohort included 1,966 SPRINT-eligible ACCORD-BP participants (40% women) with a mean age of 63 years. The mean SBP achieved after randomization was 120 ± 14 mm Hg and 134 ± 15 mm Hg in the intensive and standard arms, respectively. The kidney composite outcome occurred at a rate of 9.5 events and 7·2 events per 1,000 person-years in the intensive and standard BP arms (HR [95% CI]: 1·35 [0·85-2.14]; P = 0·20). Intensive SBP lowering did not have an effect on the risk of moderately (HR [95% CI]: 0·96 [0·76-1·20]) or severely (HR [95% CI]: 0·92 [0·66-1·28]) increased albuminuria. Including SPRINT participants with prediabetes in the cohort did not change the overall results. Conclusion: This post-hoc subgroup analysis suggests that intensive SBP lowering does not increase the risk of major adverse kidney events in individuals with T2DM and cardiovascular risk factors.

Supplemental Digital Content is available in the text., Longer time in target range (TTR) for systolic blood pressure (SBP) is associated with a lower risk of cardiovascular events. Team-based care improves SBP control but its effect on the consistency of SBP control over time is unknown. This post hoc analysis used data from a cluster-randomized trial of a physician/pharmacist collaborative model that randomized medical offices to either a 9- or 24-month pharmacist intervention or control group. TTR for SBP was calculated using linear interpolation and an SBP range of 110 to 130 mm Hg. TTR is reported as median values and group comparisons assessed using the Kruskal-Wallis test. Of the 625 participants enrolled, 524 had 9-month and 366 had 24-month SBP data. Participants were a median 59 years old, 59% female, and 52% minority. After 24 months, the median TTR for SBP was 31.9% and 29.8% for the 9- and 24-month intervention groups, respectively, compared with 19% in the control group (P=0.0068). This observation persisted in the subgroup of participants with diabetes or chronic kidney disease and minorities. A longer TTR was not associated with an increased risk of adverse drug events. Time to first observed SBP in the target range was shorter in the intervention group compared with control (270 versus 365 days; P=0.0047). A physician/pharmacist collaborative care model achieved longer TTR for SBP compared with control (usual care).

Complementary and alternative medicines (CAM) are commonly used across the world by diverse populations and ethnicities but remain largely unregulated. Although many CAM agents are purported to be efficacious and safe by the public, clinical evidence supporting the use of CAM in heart failure remains limited and controversial. Furthermore, health care professionals rarely inquire or document use of CAM as part of the medical record, and patients infrequently disclose their use without further prompting. The goal of this scientific statement is to summarize published efficacy and safety data for CAM and adjunctive interventional wellness approaches in heart failure. Furthermore, other important considerations such as adverse effects and drug interactions that could influence the safety of patients with heart failure are reviewed and discussed.

Induction in heart transplant (HT) patients is non-uniform, with center-specific protocols often dictating use and selection of agents according to patient-specific immunologic risk factors. Data regarding the evolution of induction practice patterns after the 2018 allocation system change are not available. We evaluated whether the new allocation system altered induction practice patternsaffected outcomes in adult HT recipients.We included adults (18+ years of age) who had undergone HT and received induction immunosuppression and were stratified based on surgery being before (January 1st 2015-May 31st 2018) and after (May 1st 2018-December 31st, 2021) the UNOS allocation policy change. Outcomes of 30-day mortality, 1-year mortality, and 1-year graft failure were compared between those transplanted before and after the policy change through risk-adjusted Cox proportional hazards models while drug-treated rejection in the first year was compared using multiple logistic regression.Of the 7,845 HT recipients who received induction therapy, 5,070 (64.6%) were transplanted before and 2,775 (35.4%) after the UNOS policy change. The most used induction agents were basiliximab (56.0%) and thymoglobulin (39.3%), with thymoglobulin used more often in the new (43.1%) than old system (37.2%; p0.001). Among adult HT recipients who received induction, risk-adjusted hazards of 30-day mortality (HR 0.89, 95% CI 0.67-1.18), 1-year mortality (HR 1.00, 95% CI 0.84-1.19), and 1-year graft failure (HR 0.83, 95% CI 0.60-1.15) were similar between the old and new systems. Conversely, the adjusted odds of drug-treated rejection in the first year was lower in the new system (OR 0.52, 95% CI 0.38-0.72).HT recipients in the new allocation system were more likely to receive thymoglobulin induction, which may be associated with a reduced risk of drug-treated rejection.

Body mass index (calculated as kilograms body weight divided by the square of heightin meters) is a known predictor of mortality after adult heart transplant but has limitations.We investigated whether inclusion of an explicit weight-height interaction effect improves prediction of mortality after heart transplant compared with body mass index.We included a cohort of 46424 adults who had undergone heart transplant as documented in the United Network for Organ Sharing database. Risk-adjusted prediction models for 1-year and 5-year mortality were constructed, one with the flexible weight-height interaction and the other with the body mass index. Overall model performance (R2) and discrimination (the Harrell concordance probability C index and the Somers Dxy rank correlation) were calculated. Compared with the body mass index model, the weight-height model had slightly improved overall performance (R2, 0.316 vs 0.313) and 1-year mortality discrimination (optimism- corrected Harrell C, 0.642 vs 0.640; Somers Dxy, 0.284 vs 0.281). Compared with the body mass index model, the weight-height model had improved overall performance (R2, 0.232 vs 0.224) and similar discrimination (optimism-corrected Harrell C, 0.600 vs 0.599; Somers Dxy, 0.200 vs 0.197) for 5-year mortality.Allowance for a flexible relationship between height and weight did not appreciably improve mortality prediction after heart transplant, versus body mass index, although additionalresearch is warranted.

Wildfires are increasing with human-induced climate change, but could this be ecologically beneficial in landscapes where recent fire is deficient relative to historical? I compiled 1980–2020 fire data for the San Juan Mountains, Colorado. I analyzed fire sizes and trends in area burned and fire severity, and compared fire density and rotations between 1980–2010 and 2011–2020 among ecosystem types and watersheds. I compared historical (pre-industrial) evidence from tree-ring, charcoal, and land-survey reconstructions to evaluate whether recent fire is outside the historical range of variability (HRV). Nearly all burned area was in the southwestern San Juans in 5 of 41 years and 35 of 4716 wildfires. Between 1980–2010 and 2011–2020, fire densities increased ∼200% and rotations shortened to ∼25%, similarly among ecosystems and watersheds, consistent with climatic effects. Fire rotations in 2011–2020 were within HRV for three ecosystems and deficient for four. Fire sizes and severities were within HRV. Moderate- and high-severity fire had no significant trend. Thus, reducing fire size or severity is currently ecologically unnecessary. Instead, incorporating fire from climate change, via wildland fire use, supplemented by prescribed burning, could feasibly restore historical fire regimes in most San Juan landscapes by 2050, the target of the Paris 1.5 °C goal.

Fire-prone dry forests often face increasing fires from climate change with low resistance and resilience due to logging of large, old fire-resistant trees. Their restoration across large landscapes is constrained by limited mature trees, physical settings, and protection. Active restoration has been costly and shown limited effectiveness, but lower cost passive restoration is less studied. I used GIS and machine learning to see whether passive restoration of old trees could overcome constraints in time, by 2060, across 667,000 ha of montane forests in the San Juan Mountains, Colorado, where temperatures are increasing faster than the global average. Random Forest models of physical locations of reconstructed historical old growth (OG) and relatively frequent fire (RFF) show historical OG with RFF was favored between 6.1 and 7.9℃ annual mean temperatures. Random Forest models projected that similar temperature-suitable locations were moved into the current middle montane ca 2015, and would be extended to just below the upper limit of the montane if the Paris 1.5℃ goal is reached, but beyond if not. US Forest Service common stand exam data, which covered ~15% of the study area and included 26,149 tree ages, show the highest potential for restoring resistance and resilience from old trees is a ≥120-year age class. This class could become a ≥160-year age class, which meets old-growth age criteria, over 81% of the area by ca 2060, nearly fully restoring historical old-growth levels. Half this age class is already protected, and much of the remainder could be retained using evidence-based diameter caps. Datasets thus are sufficient to show that passive restoration of old-tree resistance and resilience to fire is feasible by ca 2060 across a large montane landscape, although contingent on global success in achieving the Paris 1.5℃ goal. Passive restoration may be viable elsewhere.

OBJECTIVE To examine if older age (>70 years) should be a relative contraindication for heart transplantation, we evaluated the characteristics and outcomes of patients with age ≥70 years listed for heart transplantation; and whether post-transplantation survival was inferior to younger counterparts. DESIGN Retrospective cohort analysis. SETTING The scientific registry of transplant recipients (SRTR). PARTICIPANTS Adults (≥18 years) listed for heart transplantation in the SRTR between 2000 and 2018. INTERVENTIONS Heart transplantation. MEASUREMENTS Characteristics and outcomes were compared for adults ≥70 years and

PURPOSE Effect of pre-transplant amiodarone use on post-heart transplant (HT) survival is not well established. We therefore sought to examine the effect of amiodarone use on post-HT survival. METHODS We stratified adults who underwent HT between January 2000 and August 2018 in the Scientific Registry of Transplant Recipients according to pre-transplant amiodarone use and used recipient and donor characteristics to calculate propensity scores. We then used overlap propensity score weighting to construct Cox proportional hazards regression models (adjusted for Index for Mortality Prediction After Cardiac Transplantation [IMPACT] score and donor/recipient predicted heart mass [PHM] ratio) for mortality outcomes. Logistic regression was used to compare the odds of primary graft failure and drug-treated rejection. RESULTS 25,394 adult HT recipients were included; median (inter-quartile range) age was 55 (46, 62) years and 75.5% were men. Compared with nonusers, amiodarone users had a significantly higher prevalence of hypertension (46.7% vs. 50.2%; p

The structure and fire regime of pre-industrial (historical) dry forests over ~26 million ha of the western USA is of growing importance because wildfires are increasing and spilling over into communities. Management is guided by current conditions relative to the historical range of variability (HRV). Two models of HRV, with different implications, have been debated since the 1990s in a complex series of papers, replies, and rebuttals. The “low-severity” model is that dry forests were relatively uniform, low in tree density, and dominated by low- to moderate-severity fires; the “mixed-severity” model is that dry forests were heterogeneous, with both low and high tree densities and a mixture of fire severities. Here, we simply rebut evidence in the low-severity model’s latest review, including its 37 critiques of the mixed-severity model. A central finding of high-severity fire recently exceeding its historical rates was not supported by evidence in the review itself. A large body of published evidence supporting the mixed-severity model was omitted. These included numerous direct observations by early scientists, early forest atlases, early newspaper accounts, early oblique and aerial photographs, seven paleo-charcoal reconstructions, ≥18 tree-ring reconstructions, 15 land survey reconstructions, and analysis of forest inventory data. Our rebuttal shows that evidence omitted in the review left a falsification of the scientific record, with significant land management implications. The low-severity model is rejected and mixed-severity model is supported by the corrected body of scientific evidence.

Coronary allograft vasculopathy (CAV) continues to afflict a high number of heart transplant (HT) recipients, and elevated LDL is a key risk factor. Many patients cannot tolerate statin medications after HT; however, data for alternative agents remains scarce. To address this key evidence gap, we evaluated the safety and efficacy of the PCSK9i after HT through systematic review and meta-analysis. We searched Medline, Cochrane Central, and Scopus from the earliest date through July 15th, 2021. Citations were included if they were a report of PCSK9i use in adults after HT and reported an outcome of interest. Outcomes included change in LDL cholesterol from baseline, incidence of adverse events, and evidence of CAV. Changes from baseline and outcome incidences were pooled using contemporary random-effects model methodologies. A total of six studies including 97 patients were included. Over a mean follow-up of 13 months (range 3-21), PCSK9i use lowered LDL by 82.61 mg/dL (95% CI - 119.15 to - 46.07; I

News and social media platforms have implicated dietary supplements in the treatment and prevention of coronavirus disease 2019 (COVID-19). During this pandemic when information quickly evolves in the presence of contradicting messages and misinformation, the role of the pharmacist is essential. Here, we review theoretical mechanisms and evidence related to efficacy and safety of select supplements in the setting of COVID-19, including vitamin C, vitamin D, zinc, elderberry, and silver. Evidence evaluating these supplements in COVID-19 patients is lacking, and providers and patients should not rely on dietary supplements to prevent or treat COVID-19. Rather, reference to evidence-based guidelines should guide treatment decisions.

Background There is a paucity of contemporary data assessing the implications of atrial fibrillation (AF) on major adverse cardiovascular events (MACE) in patients with or at high‐risk for atherosclerotic disease managed in routine practice. Hypothesis We sought to evaluate the 4‐year incidence of MACE in patients with or at risk of atherosclerotic disease in the presence of AF. Methods Using US MarketScan data, we identified AF patients ≥45 years old with billing codes indicating established coronary artery disease, cerebrovascular disease, or peripheral artery disease or the presence of ≥3 risk factors for atherosclerotic disease from January 1, 2013 to December 31, 2013 with a minimum of 4‐years of available follow‐up. We calculated the 4‐year incidence of MACE (cardiovascular death or hospitalization with a primary billing code for myocardial infarction or ischemic stroke). Patients were further stratified by CHA2DS2‐VASc score and oral anticoagulation (OAC) use at baseline. Results We identified 625,951 patients with 4‐years of follow‐up, of which 77,752 (12.4%) had comorbid AF. The median (25%, 75% range) CHA2DS2‐VASc score was 4 (3, 5) and 64% of patients received an OAC at baseline. The incidence of MACE increased as CHA2DS2‐VASc scores increased (P‐interaction

OBJECTIVE To perform a systematic literature review and indirect treatment comparison (ITC) to identify, summarize and quantify randomized controlled trial (RCT) evidence evaluating combination anticoagulant or P2Y12 inhibitor with low-dose aspirin versus low-dose aspirin alone for the prevention of atherothrombotic events in patients with stable coronary artery disease (CAD) and/or peripheral artery disease (PAD). METHODS We performed an updated search of CENTRAL, MEDLINE and EMBASE through 23 August 2021 to identify RCTs of adult patients with chronic CAD and/or PAD that compared combination anticoagulant or P2Y12 inhibitor with low-dose aspirin to low-dose aspirin alone. Outcomes of interest included major adverse cardiovascular events (MACEs) including cardiovascular death, stroke, or myocardial infarction (MI) and bleeding. When needed, outcomes were pooled using random-effects models to generate hazard or risk ratios (HRs or RRs) and accompanying 95% confidence intervals (CIs). Adjusted ITCs using subsequent pooled HRs/RRs were then performed. RESULTS Six publications reporting the results of two unique RCTs (one evaluating clopidogrel + aspirin vs. aspirin alone and the other rivaroxaban 2.5 mg twice daily + aspirin vs. aspirin alone) were analyzed. The ITC suggested that rivaroxaban + aspirin was associated with a lower risk of MACEs compared with clopidogrel + aspirin (HR = 0.82, 95% CI = 0.68-0.98). When looking at the individual components of MACE, rivaroxaban + aspirin was associated with lower risk of cardiovascular death (HR = 0.75, 95% CI = 0.57-0.98) and stroke (RR = 0.67, 95 CI = 0.49-0.93) and similar risk of MI (RR = 0.93, 95% CI = 0.70-1.23) versus clopidogrel + aspirin. No evidence of a difference in moderate-to-severe bleeding, fatal bleeding or intracranial hemorrhage (ICH) was seen between the two treatment strategies. CONCLUSIONS Compared to clopidogrel + low-dose aspirin, the use of rivaroxaban 2.5 mg twice daily + low-dose aspirin reduced the risk of MACE, CV death and stroke including ischemic stroke in patients with or at high risk for chronic CAD and/or PAD. These benefits of rivaroxaban 2.5 mg twice daily + low-dose aspirin compared to clopidogrel + low-dose aspirin appear to be achieved without significantly increasing patients' risk of moderate-to-severe bleeding, including ICH or fatal bleeding.

The advent of monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) ushered in a new era of dyslipidemia pharmacotherapy. The first two antibodies targeting PCSK9 (evolocumab, alirocumab) approved by the United States Food and Drug Administration (FDA) provided significant and sustained reductions in atherogenic lipids and a reduced risk of atherosclerotic cardiovascular disease (ASCVD) events. More recently, phase 3 trials of inclisiran-a small interfering RNA-based agent targeting PCSK9-reported similar lipid-lowering effects and preliminary evidence of ASCVD risk reduction, although significant questions remain regarding the extent of benefits across cardiovascular outcomes. We conducted a systematic review and meta-analysis (random-effects model) of the available data on lipid lowering, incidence of atherosclerotic cardiovascular disease (ASCVD) events, and safety of pharmacologic agents targeting PCSK9. A significant and consistent reduction in low-density lipoprotein cholesterol (LDL-C) was observed across all agents (-51% [95% confidence interval {CI}: -61%, -41%]). Despite the impressive reduction in LDL-C, the individual effects on mortality, cardiovascular death, myocardial infarction (MI), and stroke remained nonsignificant. However, a consistent reduction was observed in the composite outcomes of MI, stroke, and cardiovascular death [relative risk {RR} (95% CI): 0.80 (0.73-0.87)] and MI, stroke, unstable angina (requiring revascularization), and cardiovascular death [RR (95% CI): 0.85 (0.74-0.97)]. In terms of safety outcomes, there was no significant difference in severe adverse events, new onset diabetes, neurocognitive disorders, or myalgia. Meanwhile, injection site reaction was more frequent in patients receiving these agents compared to placebo [RR 2.11 (95% CI): 1.26-3.54]. These findings suggest a class effect for favorable lipid changes and a low risk of serious adverse events among pharmacologic agents targeting PCSK9. Although there is compelling evidence that PCSK9-targeting agents reduce the risk of some cardiovascular outcomes, adequately powered studies with longer follow-up may be needed to fully characterize the magnitude of benefits across the cardiovascular spectrum.

Introduction: Hypertension associates with both kidney and cardiovascular (CV) disease risk. Time-in-target range (TTR) associates with CV risk independent of mean SBP and SBP variability. We hypothesized that SBP TTR predicts both adverse kidney and CV outcomes. Methods: ACCORD BP and SPRINT trial participants with >=2 SBP measurements were eligible, except ACCORD standard BP lowering participants due fewer SBP measurements. SBP TTR for months 0-3 was calculated using Rosendaal linear interpolation with target ranges of 110-130 mm Hg and 120-140 mm Hg for participants in the intensive or standard arms, respectively. Adverse kidney outcomes included dialysis, kidney transplant, serum creatinine > 3.3 mg/dL, sustained eGFR of < 15 mL/min per 1.73 m 2 or sustained eGFR decline >40% after month 3. Adverse CV outcomes included myocardial infarction, stroke, heart failure and CV death. Cox proportional hazards regression models were used to estimate the association between TTR and adverse outcomes after demographics, clinical risk factors and baseline SBP adjustment Results: Participants with higher TTR were younger, less likely to have preexisting CV disease and had less albuminuria, higher eGFR and lower baseline SBP. In fully adjusted models accounting for baseline SBP, higher TTR independently associated with a lower risk of adverse kidney and CV outcomes (P-trend < .001 for each). Whereas the relationship between TTR and CV risk increased monotonically with higher TTR, the TTR association with kidney risk was greatest at the extremes of TTR ( Figure ). Conclusions: Further reductions in adverse kidney and CV outcomes may be achievable through sustained SBP control.

Heart failure (HF) is a major cause of morbidity and mortality with more than 5.1 million individuals affected in the USA. Ventricular tachyarrhythmias (VAs) including ventricular tachycardia and ventricular fibrillation are common in patients with heart failure. The pathophysiology of these mechanisms as well as the contribution of heart failure to the genesis of these arrhythmias is complex and multifaceted. Myocardial hypertrophy and stretch with increased preload and afterload lead to shortening of the action potential at early repolarization and lengthening of the action potential at final repolarization which can result in re-entrant ventricular tachycardia. Myocardial fibrosis and scar can create the substrate for re-entrant ventricular tachycardia. Altered calcium handling in the failing heart can lead to the development of proarrhythmic early and delayed after depolarizations. Various medications used in the treatment of HF such as loop diuretics and angiotensin converting enzyme inhibitors have not demonstrated a reduction in sudden cardiac death (SCD); however, beta-blockers (BB) are effective in reducing mortality and SCD. Amongst patients who have HF with reduced ejection fraction, the angiotensin receptor-neprilysin inhibitor (sacubitril/valsartan) has been shown to reduce cardiovascular mortality, specifically by reducing SCD, as well as death due to worsening HF. Implantable cardioverter-defibrillator (ICD) implantation in HF patients reduces the risk of SCD; however, subsequent mortality is increased in those who receive ICD shocks. Prophylactic ICD implantation reduces death from arrhythmia but does not reduce overall mortality during the acute post-myocardial infarction (MI) period (less than 40 days), for those with reduced ejection fraction and impaired autonomic dysfunction. Furthermore, although death from arrhythmias is reduced, this is offset by an increase in the mortality from non-arrhythmic causes. This article provides a review of the aforementioned mechanisms of arrhythmogenesis in heart failure; the role and impact of HF therapy such as cardiac resynchronization therapy (CRT), including the role, if any, of CRT-P and CRT-D in preventing VAs; the utility of both non-invasive parameters as well as multiple implant-based parameters for telemonitoring in HF; and the effect of left ventricular assist device implantation on VAs.

Aims There are scarce data evaluating the effectiveness and safety of rivaroxaban vs. warfarin in non-valvular atrial fibrillation (NVAF) patients with concomitant coronary artery disease (CAD) and/or peripheral artery disease (PAD) treated in routine practice. Methods and results Using MarketScan data from January 2012 to December 2017, we identified oral anticoagulant (OAC)-naïve NVAF patients receiving rivaroxaban (15–20 mg once daily) or warfarin, with comorbid CAD and/or PAD and ≥12 months of insurance coverage before OAC initiation. Differences in baseline covariates between cohorts were adjusted using inverse probability-of-treatment weights based on propensity scores (standardized differences Conclusion Among patients with NVAF and comorbid CAD and/or PAD, rivaroxaban use was associated with a reduced risk of MTVEs vs. warfarin, without significantly increasing major bleeding risk.

Patients with nonvalvular atrial fibrillation with stage 4 or 5 chronic kidney disease or undergoing hemodialysis were excluded from phase III randomized trials of nonvitamin K antagonist oral anticoagulants (NOACs). We sought to evaluate the effectiveness and safety of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation and stage 4 or 5 chronic kidney disease or undergoing hemodialysis in routine practice.Using MarketScan data from January 2012 to December 2017, we identified patients on oral anticoagulant (OAC) with naïve nonvalvular atrial fibrillation and stage 4 or 5 chronic kidney disease or undergoing hemodialysis and with ≥12 months of insurance coverage before OAC initiation. Differences in baseline covariates between the rivaroxaban and warfarin cohorts were adjusted using inverse probability-of-treatment weights based on propensity scores calculated using generalized boosted models and 10,000 regression trees (absolute standardized differences0.1 achieved for all covariates after adjustment). Patients were followed until a stroke/systemic embolism or major bleeding event, OAC discontinuation/switch, insurance disenrollment, or end of data availability. Hazard ratios (HRs) and 95% confidence intervals (CIs) comparing the OAC cohorts were calculated using Cox regression.We identified 1896 rivaroxaban (38.7% received a dose20 mg/d) and 4848 warfarin users. Eighty-eight percent of included patients had stage 5 chronic kidney disease or were undergoing hemodialysis. Rivaroxaban did not significantly reduce stroke or systemic embolism (HR = 0.55, 95% CI = 0.27-1.10) or ischemic stroke (HR = 0.67, 95% CI = 0.30-1.50) alone, but it was associated with a significant 32% (95% CI = 1-53%) reduction in major bleeding risk compared with warfarin.Among patients with nonvalvular atrial fibrillation and stage 4 or 5 chronic kidney disease or undergoing hemodialysis, rivaroxaban appears associated with significantly less major bleeding compared to warfarin.

Aim To assess the impact of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on renal and mortality outcomes in people with Type 2 diabetes and proteinuria. Methods A literature search up to 6 June 2019 was performed. We included randomized trials of ≥100 participants with Type 2 diabetes and micro- or macroalbuminuria comparing an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker with placebo ± background anti-hypertensives or non-angiotensin-converting enzyme inhibitor or angiotensin receptor blocker-containing anti-hypertensives, which included follow-up of ≥12 months. Endpoints included doubling of serum creatinine, end-stage renal disease, all-cause and cardiovascular mortality and progression and regression of proteinuria. A Hartung-Knapp random-effects model (between-study variance calculated using the Paule-Mandel estimator) producing a risk ratio with 95% confidence interval was employed. Results The use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker was not associated with a significant reduction in the risk of a doubling in serum creatinine (n = 7 trials, RR = 0.77, 95% CI = 0.50-1.21). Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers reduced the risk of progressing to end-stage renal disease (n = 8, RR = 0.79, 95% CI = 0.75-0.83). No difference in all-cause (n = 11, RR = 0.98, 95% CI = 0.89-1.08) or cardiovascular mortality (n = 6 trials, RR = 1.08, 95% CI = 0.92-1.28), nor the composite outcome of doubling in serum creatinine, end-stage renal disease or mortality (n = 3 trials, RR = 0.87, 95% CI = 0.72-1.06), was observed. Progression of proteinuria was decreased with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use vs. control (n = 10, RR = 0.49, 95% CI = 0.33-0.74). Regression of proteinuria was not improved with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (n = 11, RR = 1.55, 95% CI = 0.93-2.58). Conclusion Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may reduce the risk of end-stage renal disease and slow the progression of nephropathy, but they do not appear to decrease all-cause or cardiovascular mortality in people with Type 2 diabetes and proteinuria.

Background: Ablation therapy is the treatment of choice in antiarrhythmic drugrefractory atrial fibrillation (AF). It is performed by either cryoballoon ablation (CBA) or radiofrequency ablation. CBA is gaining popularity due to simplicity with similar efficacy and complication rate compared with RFA. In this meta-analysis, we compare the recurrence rate of AF and the complications from CBA versus RFA for the treatment of AF. Methods: We systematically searched PubMed for the articles that compared the outcome of interest. The primary outcome was to compare the recurrence rate of AF between CBA and RFA. We also included subgroup analysis with complications of pericardial effusion, phrenic nerve palsy and cerebral microemboli following ablation therapy. Results: A total of 24 studies with 3527 patients met our predefined inclusion criteria. Recurrence of AF after CBA or RFA was similar in both groups (RR: 0.84; 95% CI: 0.65, 1.07; I2=48%, Cochrane p=0.16). In subgroup analysis, heterogeneity was less in paroxysmal AF (I2=0%, Cochrane p=0.46) compared to mixed AF (I2=72%, Cochrane p=0.003). Procedure and fluoroscopy time was less by 26.37 and 5.94 minutes respectively in CBA compared to RFA. Complications, pericardial effusion, and silent cerebral microemboli, were not different between the two groups, however, phrenic nerve palsy was exclusively present only in CBA group. Conclusion: This study confirms that the effectiveness of CBA is similar to RFA in the treatment of AF with the added advantages of shorter procedure and fluoroscopy times.

OBJECTIVES To assess adverse effects of pharmacologic antidepressants for treatment of major depressive disorder (MDD) in adults 65 years of age or older. DESIGN Systematic review and meta-analysis. SETTING Specialist or generalist outpatient setting, rehabilitation facility, and nursing facilities. PARTICIPANTS Persons 65 years and older with MDD. INTERVENTION Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), bupropion, mirtazapine, trazodone, vilazodone, or vortioxetine compared with another antidepressant, placebo, or nonpharmacologic therapy. MEASUREMENTS Adverse events, arrhythmias, cognitive impairment, falls, fractures, hospitalization, mortality, QTc prolongation, serious adverse events, and withdrawals due to adverse events. RESULTS Nineteen randomized controlled trials and two observational studies were included. Most studies evaluated treatment of the acute phase (

Background Historically, there is perceived pressure to achieve therapeutic levels of tacrolimus quickly after heart transplant (HT). We evaluated the association between time within therapeutic tacrolimus range and time to therapeutic trough and rejection in the 30 days following HT. Methods This is a single-center retrospective cohort study of consecutive adult HT patients receiving immunosuppression. Goal trough tacrolimus levels were 10-15 ng/ml. Surveillance endomyocardial biopsies were performed weekly for 4 weeks. Outcomes included the effect of time to and time-in-therapeutic tacrolimus range (Rosendaal method) on 30-day clinical rejection, 1R/1B, and 2R or higher histologic occurrences. Results We reviewed 67 HT patients (median age 58.8 yrs). For clinical rejection versus no-rejection groups, the median (25th, 75th percentile) time to therapeutic tacrolimus levels was 9.5 (8, 12.3) days versus 9.0 (7, 13) days (p=0.623). The median time-in-therapeutic tacrolimus range was 34.1% (23.2, 42.2) versus 36.2% (19.9, 51.2), respectively (p=0.512). Similarly, we observed no significant differences in time to and time-in-therapeutic tacrolimus range in patients who developed grade 1R/1B (p=0.650 and p=0.725) or grade 2R or higher histology (p=0.632 and p=0.933). Conclusions Our small single-center analysis suggests that neither time to nor time in therapeutic tacrolimus range predicted acute rejection within 30 days of HT.

We sought to evaluate the real-world effectiveness and safety of prolonged anticoagulation with rivaroxaban following a provoked venous thromboembolism.Using US MarketScan claims from November 2012 to March 2017, we identified adults with ≥1 primary hospitalization or emergency department diagnosis code for venous thromboembolism, a provoking (major or minor, persistent or transient) risk factor, at least 3 months of continuous rivaroxaban treatment, and ≥12 months of continuous insurance benefits prior to their qualifying venous thromboembolism. Patients were categorized as either continuing rivaroxaban or discontinuing anticoagulation (no anticoagulation or nonaspirin antiplatelet agents but may have received aspirin) after the initial 3 months of rivaroxaban treatment (index date). Differences in baseline covariates between cohorts were adjusted for using inverse probability-of-treatment weights based on propensity scores (absolute standardized differences0.1 achieved for all covariates after adjustment). Twelve month incidences of recurrent venous thromboembolism or major bleeding were compared between cohorts using Cox regression (according to an intention-to-treat methodology) and reported as hazard ratios (HRs) with 95% confidence intervals (CIs).Among patients experiencing a provoked venous thromboembolism and treated with rivaroxaban for the first 3 months (N=4,990), continued rivaroxaban use beyond 3 months (median [25%, 75% range duration of additional rivaroxaban use = 3 [2, 5] months) was associated with a 44% (95% CI of 9%-66%) lower hazard of recurrent venous thromboembolism without altering major bleeding risk [HR of 0.87, 95% CI of 0.51-1.49] versus anticoagulation discontinuation (with or without aspirin use).Our study suggests continuing rivaroxaban after the initial 3 month period was associated with a decreased risk of recurrent venous thromboembolism. The observed reduction in recurrent venous thromboembolism with prolonged rivaroxaban use was not associated with a significant change in major bleeding risk.

The coronavirus disease 2019 pandemic disrupted health care delivery in every respect, including critical care resources and the transport of patients requiring extracorporeal membrane oxygenation. Innovative solutions allowing for safe helicopter air transport of these critical patients is needed because extracorporeal membrane oxygenation resources are only available in specialty centers. We present a case demonstrating the interfacility collaboration of care for a patient with coronavirus disease 2019 infection and the lessons learned from the air transport. Careful planning, coordination, communication, and teamwork contributed to the safe transport of this patient and several others subsequently.

Objective. To determine the long-term change in the Altmetric Attention Score (AAS), and its components, as well as the impact of higher AAS on citation count for articles published in major pharmacy journals. Methods. This study evaluated articles from pharmacy journals ranked in the top 10% according to their AAS in the year 2017. Correlation between the AAS and number of citations (through November 2020) was assessed using the Spearman’s correlation test. A Kruskal-Wallis 1-way analysis of variance was used to compare the AAS across journals. Results. The median 3-year AAS and citation count per article was 20 (25th, 75th percentile = 15, 28) and 11 (6, 18), respectively. Between November 2018 and November 2020, there was no significant change in the median AAS for the 137 included articles. The only change in the AAS components was an increase in the number of Mendeley readers (22 [13, 34]). The median number of citations per article also increased (8 [4, 14]). We found a significant association between the 3-year AAS and the 3-year number of citations (adjR2=0.06). The 3-year number of Mendeley readers was associated with an increase in the 3-year number of citations (adjR2=0.36). The mean 3-year AAS was highest with articles published in the Journal of the American Pharmacists Association, while the mean 3-year number of citations was highest for articles published in Pharmacotherapy. Conclusion. Higher AAS scores appear to be associated with the number of citations for articles published in major pharmacy journals within three years of publication.

Once a routine part of atrial fibrillation (AF) management, digoxin use has declined. Likely hastening this decline are findings from several studies and systematic reviews identifying a potential association between digoxin use and all-cause mortality in AF populations. However, inconsistency exists within some of these studies potentially leading to confusion among clinicians. To critically evaluate the current literature to contextualize the associations between digoxin and mortality risk in patients with AF by performing an overview of systematic reviews. We searched MEDLINE, Cochrane Central Database of Systematic Reviews, and SCOPUS from their earliest date through October 12, 2020, to identify systematic reviews (SRs) that included studies enrolling patients with AF or atrial flutter and evaluated the association between digoxin use and all-cause mortality. We used the AMSTAR 2 tool to assess the risk of bias for each included SR. Results from reviews are qualitatively synthesized. Our search identified 10 SRs that met our inclusion criteria. Of the 41 unique AF studies included in these SRs, 41% were cohort studies, 29% were post hoc analyses of randomized controlled trials (RCTs), 15% were RCTs, and 15% were registry studies. Based on our AMSTAR 2 assessment, the overall confidence in the results of the 10 reviews was rated as "moderate" in three SRs, "low" in three SRs, and "critically low" in the rest. Except for one review, each included SR shows that digoxin use in AF is associated with a 15 to 38% higher risk of all-cause mortality. This association may be greater when AF-only populations are considered compared with a mix of AF and heart failure populations. Serum digoxin concentration (SDC) data were infrequently considered, but available data suggested a greater association between increasing SDC and all-cause mortality. This overview of reviews found general consistency regarding the association between digoxin use and higher all-cause mortality in AF populations. However, heterogeneity exists among and between SRs and an unmet need exists for additional study in a RCT setting with close monitoring and reporting of SDC to better inform clinical practice.