Evaluation of outcomes with apixaban use for venous thromboembolism in hospitalized patients with end-stage renal disease receiving renal replacement therapy.

While direct oral anticoagulants (DOACs) received expanded labeling for use in atrial fibrillation (AF) for end-stage renal disease (ESRD) based on pharmacokinetic trials, little data exist regarding the use of DOACs for venous thromboembolism (VTE) in ESRD patients requiring renal replacement therapy (RRT). This retrospective, descriptive cohort study evaluated adult patients with a diagnosis of ESRD on RRT and with a VTE diagnosis receiving apixaban therapy prior to or during admission. The primary outcome was to identify major bleeding events within 72 h of last apixaban dose administration. Secondary outcomes included new VTE while on apixaban, appropriateness of anticoagulation regimen with regards to FDA labeled dosing and frequency, anticoagulation regimen adjustments, and factor Xa inhibitor-specific anti-Xa levels if available. A total of 68 patients met criteria for inclusion in the final analysis. Major bleeding events occurred in 13.2% of patients receiving apixaban within the last 72 h. Recurrent thrombosis occurred in 7.4% of patients. The use of apixaban for VTE in patients with ESRD on RRT led to a higher risk of bleeding compared to that of landmark trials. Therefore, apixaban use should occur following shared decision making especially if there is no contraindication to warfarin.

Evaluation of Anti-Xa Apixaban and Rivaroxaban Levels With Respect to Known Doses in Relation to Major Bleeding Events.

BACKGROUND: Although not routinely recommended, anti-Xa level monitoring for apixaban or rivaroxaban may be useful in certain clinical scenarios. There are currently no laboratory standards, therapeutic ranges, or proven correlation between anti-Xa levels and clinical outcomes. OBJECTIVE: This study describes the utilization, application, and association of anti-Xa levels with clinical outcomes in patients receiving apixaban or rivaroxaban. METHODS: This retrospective, descriptive study included adult inpatients within the Houston Methodist System on apixaban or rivaroxaban with at least one anti-Xa level ordered subsequent to administered doses. The primary endpoint was major bleeding according to International Society on Thrombosis and Haemostasis criteria. Secondary endpoints included reasons for anti-Xa level ordering, anti-Xa levels at different time intervals post-dose, and thrombotic events. Pre-specified subgroup analyses were performed to further evaluate the primary endpoint. RESULTS: The study population consisted of 169 patients and 234 anti-Xa levels. Twenty-nine levels were obtained in context of major bleeding. The majority of levels were not drawn as peak levels 2-4 hours post-dose, however remained quantifiable above typical observed levels within this timeframe and well beyond 24 hours post-dose. Patient characteristics with major bleeding included elderly age, acute renal impairment, and low body weight. At least 14 unique reasons for anti-Xa level ordering were identified. Twenty-nine levels were associated with thrombotic events. CONCLUSION: Anti-Xa levels may be useful for assessment of current drug concentrations, immediate safety of therapy, and guidance for possible clinical interventions. Dose titration and reversal therapies based on anti-Xa level results in major bleeding warrant further research.

Apixaban and Rivaroxaban Anti-Xa Level Monitoring Versus Standard Monitoring in Hospitalized Patients With Acute Kidney Injury.

BACKGROUND: Oral direct factor Xa inhibitors (FxaIs) are renally eliminated; thus, acute kidney injury (AKI) may increase the risk for drug accumulation and bleeding. There is minimal data describing the effects of AKI on FxaI anti-Xa levels or clinical outcomes. OBJECTIVE: To compare anti-Xa level monitoring with standard monitoring in patients who experience AKI on apixaban or rivaroxaban. METHODS: This retrospective study included patients admitted within a large hospital system from May 2016 to October 2020. Patients were included if they received apixaban or rivaroxaban prior to AKI. Patients were stratified into 1 of 2 groups: those with anti-Xa level monitoring or those who received standard monitoring. The primary outcome was major bleeding as defined by the International Society of Thrombosis and Haemostasis. RESULTS: A total of 196 patients were included in the final analysis. Major bleeding occurred in 2 patients who received anti-Xa level monitoring, compared with 14 patients who received standard monitoring (2.1% vs 14%; P < 0.01). Variables identified as predictors of major bleeding included a documented history of liver disease (adjusted odds ratio = 3.17; 95% CI = 1.04-9.67; P = 0.04) and antiplatelet use (adjusted odds ratio = 4.18; 95% CI = 1.28-13.7; P = 0.02). CONCLUSION AND RELEVANCE: This is the first study to demonstrate that anti-Xa level monitoring was associated with a significant reduction in major bleeding compared with standard monitoring in patients with AKI who received apixaban or rivaroxaban. The optimal management of antithrombotic medications in patients with AKI and recent exposure to an FxaI requires further investigation.

Evaluation of characteristics and dosing regimens in patients with new or recurrent thrombosis on apixaban and rivaroxaban.

Direct factor Xa inhibitors, such as apixaban and rivaroxaban, are widely used for treatment and prevention of venous thromboembolism; however, recent cases of therapeutic failure have been reported. Potential risk factors associated with therapeutic failure such as dose deviations outside of package labeling recommendations, and the use of direct factor Xa-specific inhibitor levels to guide clinical decision making continue to be areas of further investigation. Our study aimed to describe characteristics and dosing regimens in patients on apixaban or rivaroxaban who experienced a new or recurrent thrombosis. We performed a retrospective chart review on 190 patients on either apixaban or rivaroxaban presenting to our institution with new or breakthrough thromboembolism. Evaluation of prescribed anticoagulation regimens compared to package labeling recommendations, direct factor Xa inhibitor-specific anti-Xa levels, anticoagulation interruptions, use of parenteral bridge anticoagulation, final anticoagulation regimen disposition, and thrombosis-associated mortality were recorded. In patients presenting with breakthrough thromboembolism, 78% were on a regimen that matched package labeling recommendations. Anti-Xa levels were documented in 66 patients, the majority of which fell within institutional expected ranges at time of thrombosis. Therapy interruptions immediately prior to thrombosis were observed in 22% of patients and 21% of those patients received parenteral anticoagulation during interruption. Upon discharge, 46% of patients continued the same anticoagulation regimen with no changes. The mortality rate was 6%. In patients who present with new thromboembolism on apixaban or rivaroxaban, a thorough review of risks and benefits should be conducted to mitigate future risk of recurrent thrombosis.

Apixaban and rivaroxaban anti-Xa level utilization and associated bleeding events within an academic health system.

BACKGROUND: Oral factor Xa inhibitors (FXaI) can be administered in fixed doses without the need for routine laboratory monitoring. Anti-Xa assays can estimate anticoagulant effect for specific FXaI's. The aim of this study was to characterize anti-Xa levels in patients taking apixaban or rivaroxaban with major bleeding events. METHODS: Apixaban and rivaroxaban anti-Xa assays ordered within our hospital system from May 2016 to September 2019 were evaluated. The primary outcome was major bleeding events defined by International Society of Thrombosis and Haemostasis criteria. Median anti-Xa levels for each FXaI were calculated for those with and without major bleeding, as well as those who did and did not receive reversal agents. RESULTS: A total of 606 anti-Xa levels were analyzed. There were 146 major bleeding events documented, with the most common site being intracranial (63%). Median anti-Xa levels in patients with and without major bleeding were similar, whereas those on apixaban therapy who received reversal agents typically had higher anti-Xa levels (73 ng/mL vs. 153 ng/mL, p = 0.0019). Factors significantly associated with increased odds of bleeding were an age > 80 years, inappropriately high dosing regimens, and modest anti-Xa levels (100-300 ng/mL) for rivaroxaban specifically. CONCLUSIONS: Older age and inappropriately high dosing regimens were associated with major bleeding in patients taking apixaban and rivaroxaban. Further investigation into the utility of anti-Xa levels for FXaI is warranted.

Meta-analysis comparing placebo responses in clinical trials of painful HIV-associated sensory neuropathy and diabetic polyneuropathy.

Background and aims The placebo response has been identified as one factor responsible for the lack of therapeutic trials with positive outcomes in neuropathic pain. Reviews have suggested that certain neuropathic pain conditions, including HIV-associated sensory neuropathy (HIV-SN), exhibit a greater placebo response than other neuropathic aetiologies. If true, such a finding could substantially affect clinical trial design and therapeutic developments for these conditions. This study aimed to identify any difference in placebo response between trials of systemic pharmacological intervention in HIV-SN and a comparable neuropathic condition, diabetic polyneuropathy (DPN) and to identify factors influencing the placebo response. Methods A systematic review search to identify randomised, double-blind studies of systemic pharmacological interventions for painful HIV-SN and DPN published between January 1966 and June 2019 was performed. A meta-analysis of the magnitude of placebo response and the proportion of placebo responders was conducted and compared between the two disease conditions. A meta-regression was used to assess for any study and participant characteristics that were associated with the placebo response. Only studies meeting a methodological quality threshold were included. Results Seventy-five trials were identified. There was no statistically significant difference in the proportion of placebo responders (HIV-SN = 0.35; versus DPN = 0.27, p = 0.129). The difference observed in the magnitude of the placebo response [pain reduction of 1.68 (1.47-1.88) DPN; 2.38 (1.87-2.98) in HIV-SN] was based on only 2 trials of HIV-SN and 35 of DPN. Potential factors influencing the placebo response such as psychological measures, were reported inconsistently. Conclusions We found no statistically significant difference in the placebo response rate between painful HIV-SN and DPN. Too few studies were available that reported the necessary information to clarify potential differences in the magnitude of placebo response or to elucidate parameters that could be contributing such differences. Implications The placebo response is one factor that may contribute to a lack of positive trials in neuropathic pain; some etiologies may display larger responses than others. This meta-analysis found no significant difference in placebo response between trials of HIV-associated sensory neuropathy and painful diabetic polyneuropathy, although limited data were available.

Evaluation of the impact of body mass index on warfarin requirements in hospitalized patients.

BACKGROUND: Despite well established empiric dose adjustments for drug and disease-state interactions, the impact of body mass index (BM) on warfarin remains unclear. The objective of this study is to evaluate warfarin requirements in hospitalized patients, stratified by BMI. METHODS: This retrospective review included two cohorts of patients: cohort A (patients admitted with a therapeutic international normalized ratio (INR)) and cohort B (newly initiated on warfarin during hospitalization). Exclusion criteria included: age under 18 years, pregnancy, INR (goal 2.5-3.5), and warfarin thromboprophylaxis post orthopedic surgery. The primary outcome was mean total weekly dose (TWD) of warfarin based on weight classification: underweight (BMI <18 kg/m2), normal/overweight (BMI 18-29.9 kg/m2), obese (BMI 30-39.9 kg/m2), and morbidly obese (BMI ⩾ 40 kg/m2). Data were extracted from two community hospitals in reverse chronologic order during July 2015-June 2013 until both study institutions evaluated 100 patients per cohort in each BMI classification or until all patients had been evaluated within the prespecified timeframe. RESULTS: A total of 585 patients were included in cohort A (26 underweight, 200 normal/overweight, 200 obese, 159 morbidly obese). There was a statistically significant difference in TWD as determined by one-way analysis of variance ( p < 0.05). A Tukey post hoc test revealed a statistically significantly higher TWD in morbidly obese (41.5 mg) compared with underweight (25.6 mg, p < 0.05), normal/overweight (28.8 mg, p < 0.05) and obese patients (32.4 mg, p < 0.05). In cohort B, 379 patients were evaluated (9 underweight, 166 normal/overweight, 152 obese, 52 morbidly obese). Overall, 191 patients had a therapeutic INR on discharge (88.9% underweight, 52.4% normal/overweight, 44.1% obese, 55.8% morbidly obese, p = 0.035). Of those, there was a statistically significant difference in TWD ( p = 0.021) with a higher TWD in the morbidly obese (41 mg) compared with underweight patients (24.4 mg, p = 0.017). CONCLUSIONS: Based on the results of this study, morbidly obese patients may require higher TWD to obtain and maintain a therapeutic INR.