Factor XI Inhibitors: Potential Role in End-Stage Kidney Disease.

Patients with end-stage kidney disease (ESKD) experience a high thrombotic risk but are also at increased risk of bleeding. There is an unmet need for safer antithrombotic therapy in patients with ESKD on hemodialysis. Factor XI (FXI) represents an attractive therapeutic target for anticoagulation because of the potential to mitigate the bleeding risks associated with currently approved anticoagulants, especially in patients at high risk of bleeding. FXI inhibition is also an attractive option in settings where coagulation is activated by exposure of the blood to artificial surfaces, including the extracorporeal circuit during hemodialysis. Therapies targeting FXI that are in the most advanced stages of clinical development include antisense oligonucleotides, monoclonal antibodies, and synthetic small molecules, which serve either to lower FXI levels or block its physiological effects. This review article presents the most recent pharmacological data with FXI inhibitors, briefly describes phase 2 and 3 clinical trials with these agents, and critically examines the potential future use of FXI inhibitors for extracorporeal circuit anticoagulation in patients with ESKD. In addition, laboratory monitoring and reversal of FXI inhibitors are briefly discussed.

Venous Thromboembolism in Exploration Class Human Spaceflight.

INTRODUCTION: A recent finding of a deep venous thrombosis during spaceflight has prompted the need to clarify mechanisms and risks of venous thromboembolism (VTE). In turn, mitigation countermeasures, diagnostic modalities, and treatment options must be explored. The objective of this review was to synthesize current evidence on VTE in spaceflight.METHODS: A literature review was performed from inception to April 2023 pertaining to VTE in the context of spaceflight or ground-based analogs with human participants. PubMed was searched for papers written in English using the terms "spaceflight" or "weightlessness" and "thrombotic" or "embolism" or "thromboembolism" in "venous" or "veins". Papers using cellular or animal models were excluded.RESULTS: There were 63 papers captured; 7 original scientific studies, 3 narrative reviews, 2 systematic reviews, and 3 commentaries discussed VTE in spaceflight. Reference lists were screened. Important themes included: altered venous hemodynamics, increased fibrinogen and coagulation markers, hypoalbuminemia, and immune dysfunction. Additional risk factors may be seen in women, such as the use of oral contraceptives.DISCUSSION: Venous stasis and decreased shear stress secondary to fluid shifts may induce inflammatory changes in the venous system, resulting in endothelial damage and upregulation of the coagulation cascade. Additionally, women in space are subject to physiological factors increasing their VTE risk, such as the use of oral contraceptives, inducing increased blood viscosity and hypoalbuminemia. Efforts should also be placed in optimizing sensitivity and specificity of imaging markers, payload, and training ability, notably the use of vector flow imaging, and improving point-of-testing biomarkers, such as albumin and p-selectin.Levasseur S, Purvis N, Trozzo S, Chung SH, Ades M, Drudi LM. Venous thromboembolism in exploration class human spaceflight. Aerosp Med Hum Perform. 2024; 95(1):45-53.

A Systematic Review and Meta-Analysis on Sex-Based Disparities in Patients with Chronic Limb Threatening Ischemia Undergoing Revascularization.

BACKGROUND: This systematic review and meta-analysis sought to describe the prognostic implications of sex on the clinical outcomes of patients undergoing interventions for chronic limb threatening ischemia (CLTI). METHODS: Studies were systematically searched across 7 databases from inception to August 25, 2021 and rerun on October 11, 2022. Studies focusing on patients with CLTI undergoing open surgery, endovascular treatment (EVT), or hybrid procedures were included if sex-based differences were associated with a clinical outcome. Two independent reviewers screened studies for inclusion, extracted data, and assessed risk of bias using the Newcastle-Ottawa scale. Primary outcomes included inpatient mortality, major adverse limb events (MALE), and amputation-free survival (AFS). Meta-analyses were performed using random effects models and reported pooled odds ratio (pOR) and 95% confidence interval (CI). RESULTS: A total of 57 studies were included in the analysis. A meta-analysis of 6 studies demonstrated that female sex was associated with statistically higher inpatient mortality compared to male sex undergoing open surgery or EVT (pOR, 1.17; 95% CI: 1.11-1.23). Female sex also demonstrated a trend toward increased limb loss in those undergoing EVT (pOR, 1.15; 95% CI: 0.91-1.45) and open surgery (pOR 1.46; 95% CI: 0.84-2.55). Female sex also had a trend toward higher MALE (pOR, 1.06; 95% CI, 0.92-1.21) in 6 studies. Finally, female sex had a trend toward worse AFS (pOR, 0.85; 95% CI, 0.70-1.03) in 8 studies. CONCLUSIONS: Female sex was significantly associated with higher inpatient mortality and a trend toward higher MALE following revascularization. Female sex trended toward worse AFS. The reasons for these disparities are likely multifaceted on patient, provider, and systemic levels and should be explored to identify solutions for decreasing these health inequities across this vulnerable patient population.

A scoping review of malnutrition in patients undergoing interventions for peripheral arterial disease.

BACKGROUND: Peripheral arterial disease (PAD) is associated with comorbid conditions and frailty. The role of preoperative nutrition in patients with PAD has not been well characterized. In the present scoping review, we sought to describe the prevalence and prognostic implications of preoperative malnutrition in patients undergoing vascular interventions for claudication or chronic limb-threatening ischemia (CLTI). METHODS: We systematically searched for studies across six databases from inception to August 2021. Studies that had focused on patients with claudication or CLTI who had undergone open or endovascular procedures were included if preoperative nutrition had been measured and correlated with a clinical outcome. RESULTS: Of 4186 records identified, 24 studies had addressed the prevalence or prognostic effects of malnutrition in patients who had undergone interventions for PAD. The proportion of women included in these studies ranged from 6% to 58%. The prevalence of preoperative malnutrition ranged from 14.6% to 72%. Seven different malnutrition assessments had been used in these studies. Across all the scales, preoperative malnutrition was associated with at least one of the following outcomes: mortality, postoperative complications, length of stay, readmission rates, and delayed wound healing. CONCLUSIONS: A variety of tools were used to measure malnutrition in patients undergoing interventions for PAD. Our findings suggest that preoperative malnutrition is associated with adverse clinical outcomes for patients undergoing open and endovascular procedures for claudication or CLTI and that consensus is lacking regarding which tool to use. Clinicians and surgeons should be sensitized to the importance of assessing for malnutrition preoperatively in adults undergoing interventions for PAD.

Frailty assessment in older adults undergoing interventions for peripheral arterial disease.

OBJECTIVE: Frailty is a multidimensional syndrome that influences postoperative morbidity and mortality after vascular procedures; however, its integration in clinical practice has been limited, given the lack of consensus on how to measure it. This study sought to compare the incremental predictive value of six different nonphysical performance frailty scales to predict poor outcomes after interventions for peripheral arterial disease (PAD). METHODS: This preplanned analysis of the FRailty Assessment In Lower Extremity arterial Disease (FRAILED) prospective cohort included two centers recruiting patients between July 1, 2015, and October 1, 2016. Individuals who underwent vascular interventions for Rutherford class 3 or higher PAD were enrolled. The following scales were compared: Edmonton Frail Scale, Groningen Frailty Indicator (GFI), modified Essential Frailty Toolset (mEFT), modified Frailty Index, Multidimensional Prognostic Index, and the Risk Analysis Index-C. The primary end point was a composite of all-cause mortality and major disability at 12 months after the procedure. The secondary end point was length of stay. Logistic regression was used to determine the association of frailty with the primary end point after adjusting for confounders. To compare the incremental predictive value of each frailty scale, model performance statistics were calculated. RESULTS: The cohort was composed of 148 patients with a mean age of 70 years. Depending on the scale used, the prevalence of frailty ranged from 16% to 70%. Frailty as measured by the GFI (adjusted odds ratio, 1.76; 95% confidence interval, 1.14-2.72) and mEFT (adjusted odds ratio, 2.71; 95% confidence interval, 1.29-5.73) predicted mortality and worsening disability at 12 months after interventions for PAD. Furthermore, there was statistically significant C-statistic, Bayesian information criterion, and integrated discrimination improvement when the GFI and mEFT were added to the baseline model. Frailty was not associated with length of stay. CONCLUSIONS: Frailty is associated with mortality and worsening disability after interventions for PAD. The GFI and mEFT performed well and identified vulnerable older adults who are at risk of poor outcomes after interventions for PAD and recommended for use in this setting.

Preoperative Exercise Rehabilitation in Cardiac and Vascular Interventions.

BACKGROUND: Exercise-based interventions have become part of the standard of care in rehabilitation programs for cardiovascular risk reduction and the promotion of a healthy lifestyle. The systematic review describes the current state of knowledge of the effects of preoperative exercise training (prehabilitation) on perioperative clinical outcomes in patients undergoing cardiac and vascular interventions. METHODS: Studies were systematically searched within 14 databases from inception to October 2016. Only studies that assessed a preoperative exercise program in adult patients undergoing cardiac or vascular interventions with clinical or patient-centered endpoints were included in the review. Two independent reviewers selected studies for inclusion, extracted data, and assessed quality using Cochrane Collaboration's tool for RCTs11111111111111111 and ROBINS-I tool for nonrandomized studies. RESULTS: Nine studies met our inclusion criteria and were stratified for qualitative analyses by cardiac (n = 7) and vascular (n = 2) procedures. Prehabilitation was associated with decreased length of stay, reduced postoperative complications, improved objective physical functioning, and improved subjective quality of life (SF-36 physical and mental health domains) measures in patients undergoing cardiac and vascular procedures. Given the amount of heterogeneity that was present in the designs, populations, and comparators among the included studies, we were unable to statistically pool data across trials. CONCLUSIONS: Our qualitative findings suggest that prehabilitation may improve clinical outcomes, physical performance, and health-related quality-of-life measures in patients undergoing cardiac and vascular surgery procedures.

Scoping review of frailty in vascular surgery.

OBJECTIVE: This review sought to describe the current state of knowledge of the impact of frailty on perioperative clinical outcomes in patients undergoing vascular interventions. METHODS: A scoping review of the literature from both PubMed and Ovid Embase databases was conducted to identify relevant English- and French-language articles published from inception to May 31, 2018. Patients undergoing vascular surgery interventions were included. RESULTS: Twenty-three studies have addressed the prevalence or prognostic impact of frailty in patients undergoing vascular surgery procedures. The prevalence of frailty ranged from 20% to 60%, and notably 14 different frailty assessments were used in these studies. Frailty was associated with increased comorbid status, prolonged length of stay, discharge to assisted living facility, loss of independence, postoperative morbidity, and all-cause mortality. CONCLUSIONS: There are a variety of heterogeneous tools to measure frailty in patients undergoing vascular surgery interventions. The prevalence of frailty varies by the scale used to measure it, as does its predictive value. Clinicians and surgeons should be sensitized to the importance of assessing frailty preoperatively in older adults undergoing vascular surgery and using it to assist in the decision-making process and allocation of surgical resources.

Interaction Between Frailty and Access Site in Older Adults Undergoing Transcatheter Aortic Valve Replacement.

OBJECTIVES: The authors sought to determine whether frail older adults undergoing nonfemoral transcatheter aortic valve replacement (TAVR) procedures had a higher risk of 30-day and 12-month mortality. BACKGROUND: Frailty can help predict outcomes and guide therapy in older adults being considered for TAVR. Nonfemoral TAVR procedures are more invasive and impart a greater risk of adverse events, which may be less well tolerated in frail patients, compared with transfemoral TAVR procedures. METHODS: This study was a post hoc analysis of the FRAILTY-AVR (Frailty Assessment Before Cardiac Surgery & Transcatheter Interventions) prospective multicenter cohort that consisted of older adults undergoing TAVR from 2012 to 2017. Frailty was assessed using the Essential Frailty Toolset (EFT). Endpoints of interest were 30-day and 12-month all-cause mortality. Interaction tables and multivariable logistic regression models were used to investigate statistical interaction on the additive and multiplicative scales. RESULTS: The cohort consisted of 723 patients with a mean age of 84 ± 6 years, of which 556 (77%) had femoral access and 167 (23%) had nonfemoral access. In frail patients with EFT scores ≥3 (35%), nonfemoral access was associated with increased 30-day mortality (odds ratio [OR]: 3.91; 95% confidence interval [CI]: 1.48 to 10.31); whereas in nonfrail patients with EFT scores <3 (65%), nonfemoral access had no effect (OR: 1.29; 95% CI: 0.34 to 4.94). There was statistical evidence of interaction between frailty and access site on 30-day mortality on the additive scale (relative excess risk due to interaction = 5.95). Nonfemoral access was associated with increased 1-year mortality in frail patients (OR: 1.98; 95% CI: 1.00 to 3.93) but not in nonfrail patients (OR: 1.83; 95% CI: 0.90 to 3.74), although there was no statistical evidence of interaction. CONCLUSIONS: Frail patients undergoing TAVR via a more invasive nonfemoral access face a substantially higher risk of 30-day mortality, whereas nonfrail older adults tolerate the procedure with a low short-term risk irrespective of access route.

Risk of Intracranial Hemorrhage Associated with the Use of Antidepressants Inhibiting Serotonin Reuptake: A Systematic Review.

BACKGROUND: Observational studies have suggested an increased risk of intracranial hemorrhage (ICH) associated with selective serotonin reuptake inhibitors (SSRIs) and other antidepressants primarily inhibiting serotonin reuptake. OBJECTIVES: Our aim was to systematically review the available epidemiologic evidence regarding the risk of ICH associated with SSRIs and antidepressants inhibiting serotonin reuptake. METHODS: MEDLINE/PubMed and EMBASE were searched for all relevant articles in English, French, or German published before April 2017. Observational studies with SSRIs or any antidepressants classified by strength of serotonin reuptake inhibition as primary exposure, a comparison group, and ICH as outcome were eligible. RESULTS: Among twelve identified studies (six nested case-control, three cohort, two case-control, one case-crossover), seven assessed the risk of ICH associated with SSRIs (some also including other antidepressants primarily inhibiting serotonin reuptake), two the risk of ICH associated with inhibitors of serotonin reuptake according to the degree of reuptake inhibition, and three addressed both objectives. Four of ten studies showed an increased risk of ICH associated with SSRIs, with the two largest studies suggesting a moderate effect. Three of five studies showed an increased risk of ICH associated with strong inhibitors of serotonin reuptake. Limitations including residual confounding, inclusion of prevalent users, potentially inappropriate study designs, and lack of power may have influenced these results, especially in studies showing no association or a highly increased risk. CONCLUSION: This systematic review suggests an increased risk of ICH with antidepressants primarily inhibiting serotonin reuptake, such as SSRIs. An increased risk of ICH with strong inhibitors of serotonin reuptake compared with weak inhibitors is also possible but the available evidence is limited. Antidepressants only moderately or weakly inhibiting serotonin reuptake might be preferred in high-risk patients.

Association of Depression With Mortality in Older Adults Undergoing Transcatheter or Surgical Aortic Valve Replacement.

Importance: Depression is increasingly recognized as a risk factor for adverse outcomes in cardiovascular disease. However, little is known about depression in older adults undergoing transcatheter (TAVR) or surgical (SAVR) aortic valve replacement. Objective: To determine the prevalence of depression and its association with all-cause mortality in older adults undergoing TAVR or SAVR. Design, Setting, and Participants: This preplanned analysis of the Frailty Aortic Valve Replacement (FRAILTY-AVR) prospective cohort study included 14 centers in 3 countries from November 15, 2011, through April 7, 2016. Individuals 70 years or older who underwent TAVR or SAVR were enrolled. Depressive symptoms were evaluated using the Geriatric Depression Scale Short Form at baseline and follow-up. Main Outcomes and Measures: All-cause mortality at 1 and 12 months after TAVR or SAVR. Logistic regression was used to determine the association of depression with mortality after adjusting for confounders such as frailty and cognitive impairment. Results: Among 1035 older adults (427 men [41.3%] and 608 women [58.7%]) with a mean (SD) age of 81.4 (6.1) years, 326 (31.5%) had a positive result of screening for depression, whereas only 89 (8.6%) had depression documented in their clinical record. After adjusting for clinical and geriatric confounders, baseline depression was found to be associated with mortality at 1 month (odds ratio [OR], 2.20; 95% CI, 1.18-4.10) and at 12 months (OR, 1.532; 95% CI, 1.03-2.24). Persistent depression, defined as baseline depression that was still present 6 months after the procedure, was associated with a 3-fold increase in mortality at 12 months (OR, 2.98; 95% CI, 1.08-8.20). Conclusions and Relevance: One in 3 older adults undergoing TAVR or SAVR had depressive symptoms at baseline and a higher risk of short-term and midterm mortality. Patients with persistent depressive symptoms at follow-up had the highest risk of mortality.

Psoas Muscle Area and Length of Stay in Older Adults Undergoing Cardiac Operations.

BACKGROUND: Frailty assessment can help predict which older adults will experience adverse events after cardiac surgical procedures. Low muscle mass is a core component of frailty that is suboptimally captured by self-reported weight loss; refined measures using computed tomographic (CT) images have emerged and are predictive of outcomes in noncardiac surgical procedures. The objective of this study was to evaluate the association between CT muscle area and length of stay (LOS) after cardiac surgical procedures. METHODS: Frail patients who had a perioperative abdominal or thoracic CT scan were identified. The CT scans were analyzed to measure cross-sectional lean muscle area at the L4 vertebra (psoas muscle area [PMA], lumbar muscle area [LMA]) and the T4 vertebra (thoracic muscle area [TMA]). The associations of PMA, LMA, and TMA with frailty markers and postoperative LOS were investigated. RESULTS: Eighty-two patients were included; the mean age was 69.2 ± 9.97 years. Low muscle area was correlated with lower handgrip strength and short physical performance battery (SPPB) scores indicative of physical frailty. Postoperative LOS was correlated with PMA (R = -0.47, p = 0.004), LMA (R = -0.41, p = 0.01), and TMA (R = -0.29, p = 0.03). After adjustment for the predicted risk of prolonged LOS, age, sex, and body surface area, PMA remained significantly associated with LOS (ß = -2.35, 95% CI -4.48 to -0.22). The combination of low PMA and handgrip strength, indicative of sarcopenia, yielded the greatest incremental value in predicting LOS. CONCLUSIONS: Low PMA is a marker of physical frailty associated with increased LOS in older adults undergoing cardiac surgical procedures. Further research is necessary to validate PMA as a prognostic marker and therapeutic target in this vulnerable population.