Asundexian: an oral small molecule factor XIa inhibitor for the treatment of thrombotic disorders.

Oral anticoagulants, including warfarin and direct oral anticoagulants, are the standard of care for thrombosis prevention and treatment; however, concerns of bleeding often dictate treatment decisions. Inhibition of the intrinsic coagulation system via factor XIa may allow for selective inhibition of the coagulation cascade without significantly impacting hemostasis after injury. Asundexian is an oral small molecule factor XIa inhibitor that, via this novel mechanism, may prove to be a safe and effective option compared with available anticoagulants. Early clinical data for asundexian was promising as a safer alternative to current therapies and prompted further analysis in certain patient populations at increased thrombotic risk. Currently, studies are ongoing to evaluate the safety and efficacy in stroke prevention in atrial fibrillation and in patients following an acute noncardioembolic ischemic stroke or high-risk transient ischemic attack.

Current oral anticoagulants have been shown to be effective for treating and preventing different clotting conditions. The disadvantage associated with these agents is an increased risk of bleeding; thus, there is a need for safer alternatives. Asundexian is a new anticoagulant that has been studied in patients after a stroke, patients with abnormal heart rhythms and patients after a heart attack in three completed clinical trials and two that are currently ongoing. Asundexian works by blocking factor XI, which is necessary for clot formation. Asundexian appears to be a promising option for preventing and treating thrombotic conditions while potentially limiting the risk of bleeding as a result of its distinct mechanism of action. The following summary explains how asundexian works and highlights the key studies showing the effects of this medication.

Development and Optimization of the Veterans Affairs' National Heart Failure Dashboard for Population Health Management.

BACKGROUND: In 2020, the Veterans Affairs (VA) health care system deployed a heart failure (HF) dashboard for use nationally. The initial version was notably imprecise and unreliable for the identification of HF subtypes. We describe the development and subsequent optimization of the VA national HF dashboard. MATERIALS AND METHODS: This study describes the stepwise process for improving the accuracy of the VA national HF dashboard, including defining the initial dashboard, improving case definitions, using natural language processing for patient identification, and incorporating an imaging-quality hierarchy model. Optimization further included evaluating whether to require concurrent ICD-codes for inclusion in the dashboard and assessing various imaging modalities for patient characterization. RESULTS: Through multiple rounds of optimization, the dashboard accuracy (defined as the proportion of true results to the total population) was improved from 54.1% to 89.2% for the identification of HF with reduced ejection fraction (HFrEF) and from 53.9% to 88.0% for the identification of HF with preserved ejection fraction (HFpEF). To align with current guidelines, HF with mildly reduced ejection fraction (HFmrEF) was added to the dashboard output with 88.0% accuracy. CONCLUSIONS: The inclusion of an imaging-quality hierarchy model and natural-language processing algorithm improved the accuracy of the VA national HF dashboard. The revised dashboard informatics algorithm has higher use rates and improved reliability for the health management of the population.

Gabapentinoid dosing and adverse events in patients with chronic kidney disease.

BACKGROUND: Gabapentinoids (GPs) are frequently prescribed in individuals with chronic kidney disease (CKD); however, their exclusive renal elimination warrants dose adjustments to decrease risk of toxicity. This study evaluated GP prescribing patterns and whether excessive dosing was associated with increased incidence of gabapentinoid-related adverse events (GRAEs). MATERIALS AND METHODS: A retrospective analysis of adult CKD and end-stage kidney disease (ESKD) patients hospitalized from 2014 to 2020 and receiving GPs was conducted. Patients were grouped based on whether the average daily dose prescribed was higher than recommended (inappropriately dosed, (ID)) or as recommended (appropriately dosed (AD)) for CKD stage. The occurrence of GRAEs was compared between groups. Patient characteristics, CKD stage, and hospital length of stay (LOS) were evaluated to determine association with GRAEs. RESULTS: The 200 patients included were predominantly female (51%), black (72%), CKD 5/ESKD (84%), and prescribed gabapentin (90%) with a mean age 61 ± 14 years. For the 111 (55%) patients in the AD group and 89 (45%) in the ID group there was no statistically significant difference in GRAEs (18 vs. 19%, p = 0.84). GRAEs were associated with older age (66 vs. 61 years; p < 0.001), seizure history (14% for GRAE vs. 3% for no GRAE, p = 0.02), and concomitant antipsychotic use (24% for GRAE vs. 5% for no GRAE; p < 0.001) but not with CKD severity. LOS was significantly longer for patients experiencing a GRAE (8.5 vs. 5.3 days; p < 0.001). CONCLUSION: Appropriate dosing of GPs is particularly important to minimize the risk of adverse events in patients of older age, with a history of seizures, or concomitant antipsychotic use. There is a need for prescriber education given the high frequency of inappropriate GP dosing observed in patients with advanced kidney disease.

Close surveillance imaging is unnecessary for patients with grade I blunt thoracic aortic injury.

BACKGROUND: No evidence-based recommendations exist for imaging surveillance of grade I blunt thoracic aortic injuries (BTAI). We aimed to evaluate the natural history of these injuries to provide guidance for follow-up imaging. METHODS: Patients that presented to our trauma center from 2008 to 2021 with grade I BTAI were retrospectively evaluated. CT angiography images were assessed for initial injury grade and subsequent stability, improvement, worsening, or resolution. RESULTS: Of 83 patients who had grade I injuries and repeat imaging, 57.8% had complete resolution, 20.5% had improvement, and 18.1% had stability of their injury. Only seven patients (8.4%) demonstrated worsening of their injury. Six patients had eventual resolution and one underwent endovascular repair that would not have been performed under current practice patterns. CONCLUSIONS: Since grade I injuries do not worsen to require later surgical intervention, early surveillance imaging is not necessary and further imaging may not be necessary at all.

Predicting Outcomes for Interhospital Transferred Patients of Emergency General Surgery.

Background: Interhospital transferred (IHT) emergency general surgery (EGS) patients are associated with high care intensity and mortality. However, prior studies do not focus on patient-level data. Our study, using each IHT patient's data, aimed to understand the underlying cause for IHT EGS patients' outcomes. We hypothesized that transfer origin of EGS patients impacts outcomes due to critical illness as indicated by higher Sequential Organ Failure Assessment (SOFA) score and disease severity. Materials and Methods: We conducted a retrospective analysis of all adult patients transferred to our quaternary academic center's EGS service from 01/2014 to 12/2016. Only patients transferred to our hospital with EGS service as the primary service were eligible. We used multivariable logistic regression and probit analysis to measure the association of patients' clinical factors and their outcomes (mortality and survivors' hospital length of stay [HLOS]). Results: We analyzed 708 patients, 280 (39%) from an ICU, 175 (25%) from an ED, and 253 (36%) from a surgical ward. Compared to ED patients, patients transferred from the ICU had higher mean (SD) SOFA score (5.7 (4.5) vs. 2.39 (2), P < 0.001), longer HLOS, and higher mortality. Transferring from ICU (OR 2.95, 95% CI 1.36-6.41, P=0.006), requiring laparotomy (OR 1.96, 95% CI 1.04-3.70, P=0.039), and SOFA score (OR 1.22, 95% CI 1.13-1.32, P < 0.001) were associated with higher mortality. Conclusions: At our academic center, patients transferred from an ICU were more critically ill and had longer HLOS and higher mortality. We identified SOFA score and a few conditions and diagnoses as associated with patients' outcomes. Further studies are needed to confirm our observation.

SGLT-2 Inhibitor Use in Heart Failure: A Review for Nurses.

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors (empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin) are a new class of heart failure medications that have previously been exclusively utilized in the management of type 2 diabetes mellitus (T2DM). The rationale for using SGLT-2 inhibitors in patients with heart failure has stemmed from recent landmark clinical trials in T2DM in which reductions in mortality and hospitalization for heart failure were first observed. On the basis of these robust outcomes, empagliflozin has further been evaluated in heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction and dapagliflozin solely in the management of HFrEF. While cardiovascular outcomes among each agent vary depending on the patient population, updates among both the American and European guidelines have included SGLT-2 inhibitors as pillars of therapy. The exact mechanisms for how SGLT-2 inhibitors are beneficial in heart failure are unknown, but current hypotheses include multiple metabolic and hemodynamic mechanisms. The purpose of this review is to summarize available literature focusing on the use of the SGLT-2 inhibitors as adjunctive therapy in heart failure, as well as evaluate mechanisms for heart failure benefit, adverse effects, and practical considerations for using these agents in the clinical setting.

Challenges of Combining Opioids and P2Y12 Inhibitors in Acute Coronary Syndrome: Should the Future Be Opioid Free?

Morphine has been long recognized as standard of care in the treatment of acute coronary syndrome (ACS) patients; however, its safety has recently been called into question due to a drug interaction with P2Y12 inhibitors. Opioids, given in combination with P2Y12 inhibitors, can reduce antiplatelet effects by slowing gastrointestinal motility and ultimately reducing drug absorption. While there are proposed benefits of opioids in ACS patients, conflicting data regarding clinical outcomes exist. The majority of clinical data slightly favors opioid use in ST-elevation myocardial infarction over non-ST-elevation myocardial infarction, although trends for increased myocardial infarction are present in both settings. Current practice should be aimed at discerning the need for routine opioid use in ACS. Alternative strategies may be needed to overcome these interactions; however, no robust data are currently available to support these treatment options. Future research should be aimed at non-opioid treatment options in ACS, as opioid use remains controversial in this population.

Factors associated with refractory pain in emergency patients admitted to emergency general surgery.

BACKGROUND: Oligoanalgesia in emergency departments (EDs) is multifactorial. A previous study reported that emergency providers did not adequately manage patients with severe pain despite objective findings for surgical pathologies. Our study aims to investigate clinical and laboratory factors, in addition to providers' interventions, that might have been associated with oligoanalgesia in a group of ED patients with moderate and severe pains due to surgical pathologies. METHODS: We conducted a retrospective study of adult patients who were transferred directly from referring EDs to the emergency general surgery (EGS) service at a quaternary academic center between January 2014 and December 2016. Patients who were intubated, did not have adequate records, or had mild pain were excluded. The primary outcome was refractory pain, which was defined as pain reduction <2 units on the 0-10 pain scale between triage and ED departure. RESULTS: We analyzed 200 patients, and 58 (29%) had refractory pain. Patients with refractory pain had significantly higher disease severity, serum lactate (3.4±2.0 mg/dL vs. 1.4±0.9 mg/dL, P=0.001), and less frequent pain medication administration (median [interquartile range], 3 [3-5] vs. 4 [3-7], P=0.001), when compared to patients with no refractory pain. Multivariable logistic regression showed that the number of pain medication administration (odds ratio [OR] 0.80, 95% confidence interval [95% CI] 0.68-0.98) and ED serum lactate levels (OR 3.80, 95% CI 2.10-6.80) were significantly associated with the likelihood of refractory pain. CONCLUSIONS: In ED patients transferring to EGS service, elevated serum lactate levels were associated with a higher likelihood of refractory pain. Future studies investigating pain management in patients with elevated serum lactate are needed.

Turning Up to Eleven: Factor XI Inhibitors as Novel Agents to Maximize Safety and Maintain Efficacy in Thromboembolic Disease.

Within the past decade nonvitamin K oral anticoagulants have emerged as the standard of care for the prevention and treatment of thromboembolic disorders, however safety of anticoagulants remain a concern for many patients and providers. There exists new interest in factor XI inhibition as novel therapeutic target based on observations of lower thrombotic rates and without significant bleed risk in individuals with inherited factor XI deficiency. Several classes of factor XI inhibitors including antisense oligonucleotides, monoclonal antibodies, and small molecule inhibitors have undergone preclinical studies and clinical trials in humans. Both osocimab and IONIS-FXI have been evaluated in patients undergoing orthopedic surgery and demonstrated superiority to enoxaparin without increasing major bleeding. Future studies with both these agents are ongoing, as well as the continued development of other inhibitors of factor XI. Early data regarding factor XI inhibition is encouraging as a potent anticoagulant and may offer a safer alternative compared to therapeutic currently available in contemporary practice for thromboembolic disease.

The Role of Colchicine in Coronary Artery Disease.

There is increasing experimental and clinical evidence that inflammation appears to play an important role in atherosclerosis and coronary artery disease. Treatment of coronary artery disease currently involves management of cardiovascular risk factors, lipid-lowering strategies and antiplatelet medications. Inflammation seems to be central to the pathogenesis of atherosclerotic plaque development, instability, and rupture seen in coronary artery disease. Colchicine, a well-known and relatively inexpensive drug, has unique anti-inflammatory properties, which is generating considerable interest in its potential role in reducing cardiovascular morbidity and potentially mortality. This review discusses the mechanism of action of colchicine in preventing and treating atherosclerosis as well as the literature from recent clinical studies supporting its use in coronary artery disease.

Changing Fields-Diabetes Medications Invading the Cardiovascular Space.

Cardiovascular disease (CVD) remains the leading cause of mortality in patients with type 2 diabetes, and treatment strategies that impact cardiovascular (CV) outcomes in this population is an area of growing interest. Pharmacologic agents that reduce CVD risk have been developed, and data supporting their use have grown extensively. Glucagon-like peptide 1 agonists and sodium-glucose cotransporter 2 inhibitors when added to metformin therapy provide the most CV benefit and should be considered in most patients. Data available suggest that sulfonylureas should be avoided in patients at risk for CVD and if a thiazolidinedione is utilized, pioglitazone may be preferred. When selecting an agent, the potential benefit, risk, and cost of each agent should be considered prior to initiation. The purpose of this review is to summarize the literature surrounding the CV effects of antidiabetic agents and to provide practical guidance on their use in patients with type 2 diabetes and CVD.

A Retrospective Comparison of 3-Factor Prothrombin Complex Concentrate Products for Warfarin Reversal.

BACKGROUND AND PURPOSE: Current guidelines suggest that 3-factor prothrombin complex concentrate is a possible alternative to 4-factor products for the emergent reversal of bleeding secondary to warfarin. While multiple observational studies have evaluated various forms of 3-factor prothrombin complex concentrate individually, no study has compared the efficacy of the 2 products. The purpose of this study is to compare the efficacy and safety of Bebulin™ and Profilnine™ for the emergent reversal of warfarin-associated major bleeding. METHODS: We conducted a retrospective cohort study of patients receiving both Bebulin™ and Profilnine™ at an urban, academic medical center with comprehensive stroke center designation and a neurosurgical center of excellence. All patients were treated at a single center that utilized a fixed, weight-based dosing protocol. The primary outcome was the percentage of patients in each group achieving a goal international normalization ratio of 1.4 or less. RESULTS: There was a significant difference in goal international normalization ratio achieved favoring Bebulin™ (85.5% vs 27.3%; P < .001) over Profilnine™. Median dose per kilogram of actual body weight was the same between the groups. When we assessed results by baseline™ international normalization ratio subgroup, more patients in the Bebulin™ group achieved goal when baseline values were 6 or less. No thrombotic events were documented in either group. CONCLUSIONS: We found that patients treated with Bebulin™ experienced significantly higher rates of successful international normalization ratio reversal when compared to those who received Profilnine™. Further research is needed to determine the comparative efficacy between the 2 agents.

The dilemma of aspirin resistance in obese patients.

Aspirin resistance (AR) commonly refers to the concept of reduced aspirin efficacy in preventing cardiovascular disease and platelet inhibition. Obesity increases the risk of heart disease three- to four-fold and has been associated with AR. Aspirin is used as a tool for both primary and secondary prevention, but recent studies suggest that its lack of efficacy for primary prevention is partly attributable to obesity. Several mechanisms have been described that contribute to AR in obese patients using pharmacokinetics and pharmacodynamics. AR may be attenuated through weight loss, alternative dosing regimens, and different drug formulations. With the global rise of obesity, it is imperative to find preventive therapies that adequately address atherosclerotic cardiovascular disease (ASCVD) risk in this population.

From WOEST to AUGUSTUS: a review of safety and efficacy of triple versus dual antithrombotic regimens in patients with atrial fibrillation requiring percutaneous coronary intervention for acute coronary syndrome.

For patients with atrial fibrillation with concomitant acute coronary syndrome (ACS) requiring percutaneous coronary intervention (PCI), the increased risk of bleeding associated with the use triple therapy is well established. However, there is question whether it is a necessary risk for patients to prevent stroke and stent thrombosis. The purpose of this article is to highlight the findings of prior studies evaluating the comparative safety and efficacy of dual and triple antithrombotic regimens in the subgroup of atrial fibrillation patients requiring PCI for ACS. Trials that evaluated dual versus triple antithrombotic therapy demonstrated post-PCI treatment with a P2Y12 inhibitor alone was safer than aspirin plus a P2Y12 inhibitor in patients also taking an anticoagulant for atrial fibrillation. Data regarding ischemic outcomes have not suggested harm with the omission of aspirin, but these studies have not been powered to assess efficacy outcomes, especially in ACS patients. These studies also demonstrate a significant reduction in bleeding events when aspirin is excluded from the post-PCI regimen in the ACS subgroup of atrial fibrillation patients. Further studies, with added focus on the ACS subgroup, are needed to potentially confirm that dual therapy may be as efficacious as triple therapy in ACS patients with atrial fibrillation.

Ticagrelor or prasugrel vs. clopidogrel in combination with anticoagulation for treatment of acute coronary syndrome in patients with atrial fibrillation.

For patients with atrial fibrillation (AF) and acute coronary syndrome (ACS), it is often challenging to find the optimal balance between the risk for ischemic and hemorrhagic complication when using both antiplatelet therapy and oral anticoagulation (OAC) with vitamin K antagonist (VKA) or direct oral anticoagulants (DOACs). Current guidelines recommended: (I) double therapy with a P2Y12 inhibitor and dose adjusted VKA is reasonable post-stenting; (II) double therapy with clopidogrel and low-dose rivaroxaban (15 mg daily) may be reasonable post-stenting; (III) double therapy with a P2Y12 inhibitor and dabigatran 150 mg twice daily is reasonable post-stenting. In the AUGUSTUS trial, most patients were given clopidogrel as part a DAPT regimen, however prasugrel and ticagrelor use allowed albeit in a small percentage of the trial population, underestimating its effect. Ticagrelor and prasugrel are known to have a stronger antiplatelet effect compared to clopidogrel, however randomized studies have not been adequately powered to date allowing comparisons between ticagrelor, prasugrel and clopidogrel together in the setting of anticoagulation for the treatment of patients with ACS and AF. Careful consideration should be given to this scenario to avoid falling into the concept of sacrificing efficacy for safety.

P2Y12 inhibitors: do they increase cancer risk?

Treatment with dual antiplatelet therapy (DAPT), typically combining a P2Y12 inhibitor with aspirin, is the standard of care for the prevention of coronary stent thrombosis, especially post revascularization and in the setting of acute coronary syndromes (ACS). Determining the appropriate duration has been debated as prolonged courses have been associated with reduced thrombotic complications. Despite proven benefit, there have been reports of a potential cancer risk associated with DAPT following the FDA's review of the TRITON-TIMI 38 trial and the DAPT trial. The latter revealed an increased risk of non-cardiovascular death, which was driven by more bleeding and cancer-related deaths. This further clouds the decision if longer courses of DAPT should be recommended. Several trials and meta-analyses have been conducted to further review this cancer risk with P2Y12 inhibitors. This manuscript intends to evaluate current literature to determine if there is a risk of cancer for patients on DAPT and its consequences in the management of cardiovascular disease.

Intravenous cangrelor as a peri-procedural bridge with applied uses in ischemic events.

Cangrelor is a relatively new antiplatelet drug that has been approved for use as an adjunct therapy to percutaneous coronary intervention (PCI) to decrease peri-procedural myocardial infarction (MI), coronary revascularization, and stent thrombosis. Cangrelor is an adenosine triphosphate analogue with a pharmacokinetic mechanism based on a reversible, dose-dependent inhibition adenosine diphosphate (ADP)-induced platelet aggregation. This drug has lately been in the spotlight as a possible bridge therapy for anti-platelet medication prior to cardiac and non-cardiac surgeries. Platelet function is usually restored within sixty minutes of cessation of therapy, thereby decreasing the risk of bleeding while providing adequate pre-procedural coverage to reduce ischemic events. This manuscript reviews the literature on cangrelor and summarizes its role as a peri-procedural bridge.

Targeting ticagrelor: a novel therapy for emergency reversal.

Newer P2Y12 inhibitors are prescribed in place of clopidogrel for patients with acute coronary syndrome (ACS) and are associated with significant bleeding risks. Currently, limited options exist for the management of life-threatening bleeding or acute reversal for patients on P2Y12 inhibitor therapy, specifically ticagrelor. Various interventions, including platelet transfusion and desmopressin, have been studied for ticagrelor reversal demonstrating limited success. PB2452 is a novel monoclonal antibody which binds to both ticagrelor and its active metabolite resulting in a rapid return of platelet aggregation. PB2452 has been studied in animal models and, most recently, in a Phase I trial in healthy volunteers. In animal models, PB2452 displayed rapid reversal of ticagrelor and its metabolites and return to near normal levels of platelet aggregation within 60 min. In healthy human volunteers, cohorts that received higher dose bolus and infusions of PB2452 over 12-16 h resulted in maximal and sustained reversal of ticagrelor inhibition of platelet aggregation. While it is currently not US Food and Drug Administration approved, future Phase 2 and 3 studies are currently underway that may lead to new directions for patients on ticagrelor therapy who require urgent reversal.