Resistant Hypertension: Disease Burden and Emerging Treatment Options.

PURPOSE OF REVIEW: To define resistant hypertension (RHT), review its pathophysiology and disease burden, identify barriers to effective hypertension management, and to highlight emerging treatment options. RECENT FINDINGS: RHT is defined as uncontrolled blood pressure (BP) ≥ 130/80 mm Hg despite concurrent prescription of ≥ 3 or ≥ 4 antihypertensive drugs in different classes or controlled BP despite prescription of ≥ to 4 drugs, at maximally tolerated doses, including a diuretic. BP is regulated by a complex interplay between the renin-angiotensin-aldosterone system, the sympathetic nervous system, the endothelin system, natriuretic peptides, the arterial vasculature, and the immune system; disruption of any of these can increase BP. RHT is disproportionately manifest in African Americans, older patients, and those with diabetes and/or chronic kidney disease (CKD). Amongst drug-treated hypertensives, only one-quarter have been treated intensively enough (prescribed > 2 drugs) to be considered for this diagnosis. New treatment strategies aimed at novel therapeutic targets include inhibition of sodium-glucose cotransporter 2, aminopeptidase A, aldosterone synthesis, phosphodiesterase 5, xanthine oxidase, and dopamine beta-hydroxylase, as well as soluble guanylate cyclase stimulation, nonsteroidal mineralocorticoid receptor antagonism, and dual endothelin receptor antagonism. The burden of RHT remains high. Better use of currently approved therapies and integrating emerging therapies are welcome additions to the therapeutic armamentarium for addressing needs in high-risk aTRH patients.

The Importance of Assessing Drug Pharmacokinetics and Pharmacodynamics in the Obese Population During Drug Development.

Obesity remains a US national health crisis and a growing concern worldwide. Concerningly, individuals who are obese are at an increased risk for comorbid diseases that include, but are not limited to, hypertension, diabetes, cardiovascular disease, and cancer. Beyond the risk for developing these conditions, obesity may also impact the pharmacological activity of the therapies being used to treat them and other disease states. The pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of therapies, both currently marketed and under clinical development, may be directly impacted by the physiological alterations that occur secondary to the occurrence of chronic excess body weight. The increased prevalence of this disease should not be ignored. Both private and federal institutions involved in drug research and development should consider, as appropriate, a greater inclusion of individuals who are obese in clinical trials throughout the entirety of drug development, and leverage the available PK, PD, safety, and efficacy data to make more informed dosing recommendations.

Rise of Ruppia in Chesapeake Bay: Climate change-driven turnover of foundation species creates new threats and management opportunities.

Global change has converted many structurally complex and ecologically and economically valuable coastlines to bare substrate. In the structural habitats that remain, climate-tolerant and opportunistic species are increasing in response to environmental extremes and variability. The shifting of dominant foundation species identity with climate change poses a unique conservation challenge because species vary in their responses to environmental stressors and to management. Here, we combine 35 y of watershed modeling and biogeochemical water quality data with species comprehensive aerial surveys to describe causes and consequences of turnover in seagrass foundation species across 26,000 ha of habitat in the Chesapeake Bay. Repeated marine heatwaves have caused 54% retraction of the formerly dominant eelgrass (Zostera marina) since 1991, allowing 171% expansion of the temperature-tolerant widgeongrass (Ruppia maritima) that has likewise benefited from large-scale nutrient reductions. However, this phase shift in dominant seagrass identity now presents two significant shifts for management: Widgeongrass meadows are not only responsible for rapid, extensive recoveries but also for the largest crashes over the last four decades; and, while adapted to high temperatures, are much more susceptible than eelgrass to nutrient pulses driven by springtime runoff. Thus, by selecting for rapid post-disturbance recolonization but low resistance to punctuated freshwater flow disturbance, climate change could threaten the Chesapeake Bay seagrass' ability to provide consistent fishery habitat and sustain functioning over time. We demonstrate that understanding the dynamics of the next generation of foundation species is a critical management priority, because shifts from relatively stable habitat to high interannual variability can have far-reaching consequences across marine and terrestrial ecosystems.

Updated Renal Dosage Recommendations for Rivaroxaban in Patients Experiencing or at Risk of Thromboembolic Disease.

Patients with chronic kidney disease are at an increased risk of venous thromboembolism (VTE). The factor Xa inhibitor rivaroxaban has been shown to provide similar efficacy and a lower risk of bleeding compared with vitamin K antagonists for the treatment and prevention of VTE. Rivaroxaban has been studied in patients with varying degrees of renal impairment, and this review summarizes current knowledge supporting its use in patients with severe renal impairment (creatinine clearance [CrCl] of 15 to < 30 mL/min) for the prevention, treatment, or prophylaxis of VTE. Clinical pharmacology studies have demonstrated an increase in rivaroxaban systemic exposure, factor Xa inhibition, and prothrombin time with decreasing renal function. These changes reach a plateau with comparable increases in exposure among individuals with moderate or severe renal impairment and end-stage renal disease. The clinical development program for the treatment and prevention of VTE as well as prophylaxis of deep vein thrombosis (DVT) following orthopedic surgery excluded patients with CrCl < 30 mL/min; however, a limited number of patients with severe renal impairment were enrolled. Efficacy outcomes in these patients with severe renal impairment were not meaningfully different from those of patients with higher levels of renal function. There was also no increase in the incidence of major bleeding with rivaroxaban in patients with CrCl < 30 mL/min. Taken together, these pharmacological and clinical data suggest that in patients with severe renal impairment, the approved dosages of rivaroxaban can be used in the treatment and prevention of VTE and for prophylaxis of DVT after hip or knee replacement surgery.

Sequential Flow Diversion After Nitinol Stent Placement for a Large, Matricidal Cavernous Internal Carotid Artery Aneurysm: Technical Video.

The Surpass Evolve flow diverter is a novel 64-wire braided intravascular stent approved to treat unruptured large or giant saccular wide-neck or fusiform intracranial aneurysms of the intracranial internal carotid artery.1-3 Flow diverting stents have been used for the treatment of previously stented aneurysms, including residual aneurysms following prior flow diversion.5-8 This patient initially presented with a large symptomatic matricidal cavernous ICA aneurysm4 that was treated with stand-alone Neuroform Atlas stenting at an outside hospital. Here we present a video demonstrating the placement of sequential Surpass Evolve flow diverter stents within a Neuroform Atlas nitinol stent.

Direct, Indirect, and Combined Extracranial-to-Intracranial Bypass for Adult Moyamoya Disease: An Updated Systematic Review and Meta-Analysis.

BACKGROUND: Moyamoya disease is a chronic, progressive cerebrovascular disease involving occlusion or stenosis of the terminal portion of the internal carotid artery. We conducted an updated systematic review and meta-analysis to investigate clinical and angiographic outcomes comparing direct, combined, and indirect bypass for the treatment of moyamoya disease in adults. METHODS: Two independent authors performed Preferred Reporting Items for Systematic reviews and Meta-Analyses guided literature searches in December 2021 to identify articles reporting clinical/angiographic outcomes in adult moyamoya disease patients undergoing bypass. Primary end points used were ischemic and hemorrhagic strokes, clinical outcomes, and angiographic revascularization. Study quality was evaluated with Newcastle-Ottawa and the Oxford Center for Evidence-Based Medicine scales. RESULTS: Four thousand four hundred fifty seven articles were identified in the initial search; 143 articles were analyzed. There were 3827 direct, 3826 indirect, and 3801 combined bypasses. Average length of follow-up was 3.59±2.93 years. Pooled analysis significantly favored direct (odds ratio [OR], 0.62 [0.48-0.79]; P<0.0001; OR, 0.44 [0.32-0.59]; P<0.0001; OR, 0.56 [0.42-0.74]; P<0.0001; OR, 3.1 [2.5-3.8]; P=0.0001) and combined (OR, 0.53 [0.41-0.69]; P<0.0001; OR, 0.28 [0.2-0.41]; P<0.0001; OR, 0.41 [0.3-0.56]; P<0.0001; OR, 3.1 [2.8-4.3]; P=0.0001) over indirect bypass for early stroke, late stroke, late intracerebral hemorrhage, and favorable outcomes, respectively. Indirect bypass was favored over combined (OR, 3.1 [1.7-5.6]; P<0.0001) and direct (OR, 4.12 [2.34-7.25]; P<0.0001) for early intracerebral hemorrhage. The meta-analysis significantly favored direct (OR, 0.37 [0.23-0.60]; P<0.001; OR, 0.49 [0.31-0.77]; P=0.002) and combined (OR, 0.23 [0.12-0.43]; P<0.00001; OR, 0.30 [0.18-0.49]; P<0.00001) bypass over indirect bypass for late stroke and late hemorrhage, respectively. Combined bypass was favored over indirect bypass for favorable outcomes (OR, 2.06 [1.18-3.58]; P=0.01). CONCLUSIONS: Based on combined meta-analysis (43 articles) and pooled analysis (143 articles), the existing literature indicates that combined and direct bypasses have significant benefits for patients suffering from late stroke and hemorrhage versus indirect bypass. Combined bypass was favored over indirect bypass for favorable outcomes. This is a strong recommendation based on low-quality evidence when utilizing the Grades of Recommendation, Assessment, Development, and Evaluation system. These findings have important implications for bypass strategy selection.

Data synthesis for environmental management: A case study of Chesapeake Bay.

Synthesizing large, complex data sets to inform resource managers towards effective environmental stewardship is a universal challenge. In Chesapeake Bay, a well-studied and intensively monitored estuary in North America, the challenge of synthesizing data on water quality and land use as factors related to a key habitat, submerged aquatic vegetation, was tackled by a team of scientists and resource managers operating at multiple levels of governance (state, federal). The synthesis effort took place over a two-year period (2016-2018), and the results were communicated widely to a) scientists via peer review publications and conference presentations; b) resource managers via web materials and workshop presentations; and c) the public through newspaper articles, radio interviews, and podcasts. The synthesis effort was initiated by resource managers at the United States Environmental Protection Agencys' Chesapeake Bay Program and 16 scientist participants were recruited from a diversity of organizations. Multiple short, immersive workshops were conducted regularly to conceptualize the problem, followed by data analysis and interpretation that supported the preparation of the synthetic products that were communicated widely. Reflections on the process indicate that there are a variety of structural and functional requirements, as well as enabling conditions, that need to be considered to achieve successful outcomes from synthesis efforts.

Effectiveness, safety, and healthcare costs associated with rivaroxaban versus warfarin among venous thromboembolism patients with obesity: a real-world study in the United States.

Prior observational studies suggest rivaroxaban is safe and effective among patients with morbid obesity who suffered a venous thromboembolism (VTE) event, but existing data are more limited in the broader population of VTE patients with obesity. This study assessed VTE recurrence, major bleeding, healthcare resource utilization, and healthcare costs among VTE patients with obesity who received rivaroxaban versus warfarin. VTE patients with obesity who initiated rivaroxaban or warfarin after a first VTE (index date) were identified from the IQVIA PharMetrics® Plus database (01/02/2011-09/30/2019). The follow-up period spanned from the index date until health plan disenrollment, end of data availability, cancer diagnosis/treatment, end of the 12 month post-index period, or (for the analysis of major bleeding) anticoagulant discontinuation or switch. Patient characteristics were balanced using inverse probability of treatment weighting. The weighted rivaroxaban (N = 8666) and warfarin cohorts (N = 5946) were well balanced (mean age = 51 years, females = 52%). Over a 9.6 months mean observation period, rivaroxaban users had a significantly lower risk of VTE recurrence [7.0% vs. 8.2%, HR(95% CI) = 0.85(0.75;0.97)] and a similar risk of major bleeding [4.1% vs. 3.6%, HR(95% CI) = 1.11(0.89;1.37)] relative to warfarin users at 12 months. Relative to warfarin users, rivaroxaban users had significantly fewer all-cause outpatient visits [RR(95% CI) = 0.71(0.70;0.74)]. The higher pharmacy costs incurred by rivaroxaban recipients (cost difference = $1252) were offset by lower medical costs (cost difference = - $2515, all p < 0.05) compared with warfarin recipients. Our findings suggest that rivaroxaban is safe and effective versus warfarin, and associated with lower medical costs among VTE patients with obesity.

Biomarker signatures in cancer patients with and without venous thromboembolism events: a substudy of CASSINI.

Cancer is associated with an increased risk of venous thromboembolism (VTE). In the CASSINI study, ambulatory cancer patients with a Khorana risk score ≥2 had a reduced risk of VTE while receiving rivaroxaban. This analysis used blood samples from CASSINI to compare biomarker levels between patients with and without VTE. VTE occurred in 62 patients during the 6 months of CASSINI (cases), and they were matched by age, sex, cancer type, tumor stage, and Khorana score to 62 controls. Baseline blood samples were analyzed for 280 biomarkers, and biomarker distribution was compared using the Wilcoxon rank-sum test between groups defined by VTE occurrence and vital status. Sparse Bayesian regression modeling was used to select a joint panel of potential VTE biomarkers. Biomarkers with the largest differences in baseline distribution among cancer patients with and without VTE included decreases in stromal cell-derived factor-1 (SDF-1), thyroid-stimulating hormone (TSH), and monocyte chemotactic protein 4 and increases in growth hormone (GH) and interleukin-1 receptor type 1 (IL-1R1). Between survivors and those who died, significantly different biomarkers included ST2, IL-8, and C-reactive protein. Regression analyses also identified decreases in SDF-1 and TSH. Pathway analysis indicated enrichment of cytokine and chemokine activity with IL-1R1, SDF-1, and GH, which are the strongest predictors of VTE or death. Our analyses highlight the interactions between hemostatic and inflammatory processes and identify candidate biomarkers of cancer-associated VTE. Prospective studies will determine clinical relevance of these biomarkers. This trial was registered at www.ClinicalTrials.gov as #NCT02555878.

Economic burden of rivaroxaban and warfarin among nonvalvular atrial fibrillation patients with obesity and polypharmacy.

Aim: Evaluate healthcare resource utilization (HRU) and costs associated with rivaroxaban and warfarin among nonvalvular atrial fibrillation (NVAF) patients with obesity and polypharmacy. Materials & methods: IQVIA PharMetrics® Plus (January 2010-September 2019) data were used to identify NVAF patients with obesity (BMI ≥30 kg/m2) and polypharmacy (≥5 medications) initiated on rivaroxaban or warfarin. Weighted rate ratios and cost differences were evaluated post-treatment initiation. Results: Rivaroxaban was associated with significantly lower rates of HRU, including hospitalization (rate ratio [95% CI]: 0.83 [0.77, 0.92]). Medical costs were reduced in rivaroxaban users (difference [95% CI]: -US$6868 [-US$10,628, -US$2954]), resulting in significantly lower total healthcare costs compared with warfarin users (difference [95% CI]: -US$4433 [-US$8136, -US$582]). Conclusion: Rivaroxaban was associated with lower HRU and costs compared with warfarin among NVAF patients with obesity and polypharmacy in commercially insured US patients.

Woven EndoBridge Embolized Aneurysm Clippings: 2-Dimensional Operative Video.

The Woven EndoBridge (WEB) device (MicroVention, Aliso Viejo, California) is an intrasaccular flow disruptor used for the treatment of both unruptured and ruptured intracranial aneurysms. WEB has been shown to have 54% complete and 85% adequate aneurysm occlusion rates at 1-yr follow-up.1 Residual and recurrent ruptured aneurysms have been shown to have a higher risk of re-rupture than completely occluded aneurysms.2 With increased utilization of WEB in the United States, optimizing treatment strategies of residual aneurysms previously treated with the WEB device is essential, including surgical clipping.3,4 Here, we present an operative video demonstrating the surgical clip occlusion of previously ruptured middle cerebral artery and anterior communicating artery aneurysms that had been treated with the WEB device and had sizable recurrence on follow-up angiography. Informed consent was obtained from both patients. Lessons learned include the following: (1) the WEB device is highly compressible, unlike coils; (2) proximal WEB marker may interfere with clip closure; (3) no evidence of WEB extrusion into the subarachnoid space; (4) no more scarring than expected in ruptured cases; and (5) clipping is a feasible option for treating WEB recurrent or residual aneurysms.

Comparative Effectiveness and Safety of Rivaroxaban and Warfarin Among Nonvalvular Atrial Fibrillation (NVAF) Patients with Obesity and Polypharmacy in the United States (US).

INTRODUCTION: Current evidence indicates that rivaroxaban may be a safe and effective alternative to warfarin among patients with nonvalvular atrial fibrillation (NVAF) and obesity. However, evidence regarding the impact of polypharmacy is limited in this population. The present study evaluated the effectiveness and safety of rivaroxaban versus warfarin among NVAF patients with obesity and polypharmacy in the US. METHODS: De-identified health insurance claims data from the IQVIA PharMetrics® Plus data (01/2010-09/2019) were used to identify NVAF patients with obesity (BMI ≥ 30 kg/m2) and polypharmacy (≥ 5 medications) initiated on rivaroxaban or warfarin. Inverse probability of treatment weighting (IPTW) was used to adjust for imbalances between groups. Study outcomes were evaluated up to 36 months post-treatment initiation and included the composite of stroke or systemic embolism (stroke/SE) and major bleeding. Subgroup analyses were conducted stratified by polypharmacy category (5-9 or ≥ 10 medications). Outcomes were assessed using Cox proportional hazards regression models with hazard ratios (HR) and 95% confidence intervals (CIs). RESULTS: A total of 7000 and 3920 NVAF patients with obesity and polypharmacy were initiated on rivaroxaban and warfarin, respectively. At 36 months of follow-up, rivaroxaban was associated with a 29% lower risk of stroke/SE relative to warfarin (HR 0.71, 95% CI 0.57, 0.90). Major bleeding risk was not significantly different among rivaroxaban- compared to warfarin-treated patients (HR 0.85, 95% CI 0.70, 1.03). Subgroup analyses yielded results that were largely consistent with the overall polypharmacy analysis. CONCLUSIONS: These results suggest that rivaroxaban is an effective and safe treatment option among NVAF patients with obesity and polypharmacy in a commercially-insured US population.

Healthcare resource utilization and costs of rivaroxaban versus warfarin among non-valvular atrial fibrillation (NVAF) patients with obesity in a US population.

AIM: To assess the real-world healthcare resource utilization (HRU) and costs of patients with non-valvular atrial fibrillation (NVAF) and obesity newly initiated on rivaroxaban or warfarin in the US. METHODS: This retrospective study used IQVIA PharMetrics Plus data (01/2010-09/2019) to evaluate patients (≥18 years) with NVAF and obesity (body mass index ≥30 kg/m2) initiated on rivaroxaban or warfarin (on or after 01/2013). Inverse probability of treatment weighting (IPTW) was used to adjust for confounding between cohorts. HRU and costs were assessed post-treatment initiation. Weighted cohorts were compared using Poisson regression models and cost differences, with 95% confidence intervals (CIs) and p values generated using non-parametric bootstrap procedures. RESULTS: After IPTW, 10,555 and 5,080 patients were initiated on rivaroxaban and warfarin, respectively (mean age: 59 years). At 12 months follow-up, the rivaroxaban cohort had lower all-cause HRU, including fewer hospitalizations (rate ratio [RR]: 0.80, 95% CI: 0.74, 0.87), emergency room visits (RR: 0.89, 95% CI: 0.83, 0.97), and outpatient visits (RR: 0.72, 95% CI: 0.69, 0.77; all p < .05). Medical costs were also reduced in the rivaroxaban cohort (mean difference: -$6,759, 95% CI: -$9,814, -$3,311) due to reduced hospitalization costs (mean difference: -$5,967, 95% CI: -$8,721, -$3,327), resulting in lower total all-cause healthcare costs compared to the warfarin cohort (mean difference: -$4,579, 95% CI: -$7,609, -$1,052; all p < .05). The rivaroxaban cohort also had lower NVAF-related HRU and medical costs driven by lower hospitalization at 12 months post-treatment initiation. HRU and cost reductions associated with rivaroxaban persisted up to 36 months of follow-up. LIMITATIONS: Claims data may have contained inaccuracies and obesity was classified based on ICD diagnosis codes given that patient BMI values were not available. CONCLUSIONS: Rivaroxaban was associated with reduced HRU and costs compared to warfarin among NVAF patients with obesity in a real-world US setting.

Real-world effectiveness and safety of rivaroxaban versus warfarin among non-valvular atrial fibrillation patients with obesity in a US population.

OBJECTIVES: Current evidence indicates that the pharmacokinetic profile of rivaroxaban is not significantly impacted by body weight. However, real-world data are needed to better assess the potential clinical benefits and risks associated with rivaroxaban in non-valvular atrial fibrillation (NVAF) patients with obesity. Thus, our objectives were to assess the real-world effectiveness and safety of rivaroxaban versus warfarin among NVAF patients with obesity in the US nationally representative commercially-insured population. METHODS: Health insurance claims data from the IQVIA PharMetrics Plus database (January 2010-September 2019) were used to identify NVAF patients with obesity (based on diagnosis codes) initiated on rivaroxaban or warfarin. Inverse probability of treatment weighting (IPTW) was used to adjust for imbalances between groups. Study outcomes of interest were evaluated up to 36 months post-treatment initiation and included the composite of stroke or systemic embolism (stroke/SE) and major bleeding. Outcomes were compared using Cox proportional hazards regression models with hazard ratios (HR) and 95% confidence intervals (CIs). RESULTS: A total of 10,555 patients were initiated on rivaroxaban and 5080 patients on warfarin. Following IPTW, the risk of stroke/SE was 26% lower among patients prescribed rivaroxaban relative to warfarin (HR: 0.74, 95% CI: 0.60, 0.91, p = .004) at 36 months. Rivaroxaban-initiated patients had a risk of major bleeding similar to that of warfarin-initiated patients (HR: 0.85, 95% CI: 0.71, 1.02, p = .085). CONCLUSIONS: These results suggest that rivaroxaban is an effective and safe treatment option among NVAF patients with obesity in a commercially-insured US population.