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Background Andexanet alfa is approved (FDA “accelerated approval”; EMA “conditional approval”) as the first specific reversal agent for factor Xa (FXa) inhibitor-associated uncontrolled or life-threatening bleeding. Four-factor prothrombin complex concentrates (4F-PCC) are commonly used as an off-label, non-specific, factor replacement approach to manage FXa inhibitor-associated life-threatening bleeding. We evaluated the effectiveness and safety of andexanet alfa versus 4F-PCC for management of apixaban- or rivaroxaban-associated intracranial hemorrhage (ICH). Methods This two-cohort comparison study included andexanet alfa patients enrolled at US hospitals from 4/2015 to 3/2020 in the prospective, single-arm ANNEXA-4 study and a synthetic control arm of 4F-PCC patients admitted within a US healthcare system from 12/2016 to 8/2020. Adults with radiographically confirmed ICH who took their last dose of apixaban or rivaroxaban < 24 h prior to the bleed were included. Patients with a Glasgow Coma Scale (GCS) score < 7, hematoma volume > 60 mL, or planned surgery within 12 h were excluded. Outcomes were hemostatic effectiveness from index to repeat scan, mortality within 30 days, and thrombotic events within five days. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using propensity score-overlap weighted logistic regression. Results The study included 107 andexanet alfa (96.6% low dose) and 95 4F-PCC patients (79.3% receiving a 25 unit/kg dose). After propensity score-overlap weighting, mean age was 79 years, GCS was 14, time from initial scan to reversal initiation was 2.3 h, and time from reversal to repeat scan was 12.2 h in both arms. Atrial fibrillation was present in 86% of patients. Most ICHs were single compartment (78%), trauma-related (61%), and involved the intracerebral and/or intraventricular space(s) (53%). ICH size was ≥ 10 mL in volume (intracerebral and/or ventricular) or ≥ 10 mm in thickness (subdural or subarachnoid) in 22% of patients and infratentorial in 15%. Andexanet alfa was associated with greater odds of achieving hemostatic effectiveness (85.8% vs. 68.1%; OR 2.73; 95% CI 1.16–6.42) and decreased odds of mortality (7.9% vs. 19.6%; OR 0.36; 95% CI 0.13–0.98) versus 4F-PCC. Two thrombotic events occurred with andexanet alfa and none with 4F-PCC. Conclusions In this indirect comparison of patients with an apixaban- or rivaroxaban-associated ICH, andexanet alfa was associated with better hemostatic effectiveness and improved survival compared to 4F-PCC. Trial registration NCT02329327; registration date: December 31, 2014.

A retrospective cohort analysis of the US MarketScan claims databases was performed to compare persistence and discontinuation rates between the vitamin K antagonist warfarin and the non-vitamin K antagonist oral anticoagulants rivaroxaban and dabigatran in patients with non-valvular atrial fibrillation. The analysis included adult patients with non-valvular atrial fibrillation newly initiated on rivaroxaban, dabigatran, or warfarin between November 1, 2011 and December 31, 2013, with a baseline CHA2DS2-VASc score ≥2, two or more non-valvular atrial fibrillation diagnosis codes (427.31), and ≥6 months' continuous medical and pharmacy benefit enrollment before oral anticoagulant initiation. Propensity score matching was performed to match patients receiving rivaroxaban with those receiving dabigatran (1:1) and warfarin (1:1). Patients were followed until the first event of inpatient death, end of continuous enrollment, or end of study period. Medication persistence was defined as absence of a refill gap of >60 days. Discontinuation was defined as no additional refill for >90 days and through to end of follow-up. Hazard ratios (HRs) of oral anticoagulant persistence and discontinuation were estimated using Cox proportional hazard models. In total, 3,2634 patients were included (n = 10878/oral anticoagulant group). Rivaroxaban was associated with better persistence than both dabigatran (HR 0.64, 95% confidence interval [CI] 0.62-0.67) and warfarin (HR 0.62, 95% CI 0.59-0.64) and lower discontinuation than dabigatran (HR 0.61, 95% CI 0.58-0.64) and warfarin (HR 0.65, 95% CI 0.62-0.68). Real-world analysis of oral anticoagulant use may reveal whether the relatively high persistence/low discontinuation demonstrated for rivaroxaban translates into lower rates of stroke.

When first line therapy with metformin is insufficient for patients with type 2 diabetes (T2D), the optimal adjunctive therapy is unclear. We assessed the efficacy and safety of adjunctive antidiabetic agents in patients with inadequately controlled T2D on metformin alone. A search of MEDLINE and CENTRAL, clinicaltrials.gov, regulatory websites was performed. We included randomized controlled trials of 3-12 months duration, evaluating Food and Drug Administration or European Union approved agents (noninsulin and long acting, once daily basal insulins) in patients experiencing inadequate glycemic control with metformin monotherapy (≥ 1500 mg daily or maximally tolerated dose for ≥ 4 weeks). Random-effects network meta-analyses were used to compare the weighted mean difference for changes from baseline in HbA1c, body weight (BW) and systolic blood pressure (SBP), and the risk of developing hypoglycemia, urinary (UTI) and genital tract infection (GTI). Sixty-two trials evaluating 25 agents were included. All agents significantly reduced HbA1c vs. placebo; albeit not to the same extent (range, 0.43% for miglitol to 1.29% for glibenclamide). Glargine, sulfonylureas (SUs) and nateglinide were associated with increased hypoglycemia risk vs. placebo (range, 4.00-11.67). Sodium glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 analogs, miglitol and empagliflozin/linagliptin significantly reduced BW (range, 1.15-2.26 kg) whereas SUs, thiazolindinediones, glargine and alogliptin/pioglitazone caused weight gain (range, 1.19-2.44 kg). SGLT2 inhibitors, empagliflozin/linagliptin, liraglutide and sitagliptin decreased SBP (range, 1.88-5.43 mmHg). No therapy increased UTI risk vs. placebo; however, SGLT2 inhibitors were associated with an increased risk of GTI (range, 2.16-8.03). Adding different AHAs to metformin was associated with varying effects on HbA1c, BW, SBP, hypoglycemia, UTI and GTI which should impact clinician choice when selecting adjunctive therapy.

Whether 30-day modified Rankin Scale (mRS) scores can predict 90-day scores is unclear. This study derived and validated a model to predict ordinal 90-day mRS score in an intracerebral hemorrhage (ICH) population using 30-day mRS values and routinely available baseline variables. Adults enrolled in the Antihypertensive Treatment of Acute Cerebral Hemorrhage-2 (ATACH-2) trial between May 2011 and September 2015 with acute ICH, who were alive at 30 days and had mRS scores reported at both 30 and 90 days were included in this post-hoc analysis. A proportional odds regression model for predicting ordinal 90-day mRS scores was developed and internally validated using bootstrapping. Variables in the model included: mRS score at 30 days, age (years), hematoma volume (cm 3 ), hematoma location (deep [basal ganglia, thalamus], lobar, or infratentorial), presence of intraventricular hemorrhage (IVH), baseline Glasgow Coma Scale (GCS) score, and National Institutes of Health Stroke Scale (NIHSS) score at randomization. We assessed model fit, calibration, discrimination, and agreement (ordinal, dichotomized functional independence), and EuroQol-5D ([EQ-5D] utility weighted) between predicted and observed 90-day mRS. A total of 898/1000 participants were included. Following bootstrap internal validation, our model (calibration slope = 0.967) had an optimism-corrected c-index of 0.884 (95% CI = 0.873–0.896) and R 2 = 0.712 for 90-day mRS score. The weighted ĸ for agreement between observed and predicted ordinal 90-day mRS score was 0.811 (95% CI = 0.787–0.834). Agreement between observed and predicted functional independence (mRS score of 0–2) at 90 days was 74.3% (95% CI = 69.9–78.7%). The mean ± SD absolute difference between predicted and observed EQ-5D–weighted mRS score was negligible (0.005 ± 0.145). This tool allows practitioners and researchers to utilize clinically available information along with the mRS score 30 days after ICH to reliably predict the mRS score at 90 days.

Apixaban was shown to be superior to adjusted-dose warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation (AF) and at least one additional risk factor for stroke, and associated with reduced rates of hemorrhage. We sought to determine the cost-effectiveness of using apixaban for stroke prevention. Based on the results from the Apixaban Versus Warfarin in Patients with Atrial Fibrillation (ARISTOTLE) trial and other published studies, we constructed a Markov model to evaluate the cost-effectiveness of apixaban versus warfarin from the Medicare perspective. The base-case analysis assumed a cohort of 65-year-old patients with a CHADS(2) score of 2.1 and no contraindication to oral anticoagulation. We utilized a 2-week cycle length and a lifetime time horizon. Outcome measures included costs in 2012 US$, quality-adjusted life-years (QALYs), life years saved and incremental cost-effectiveness ratios. Under base case conditions, quality adjusted life expectancy was 10.69 and 11.16 years for warfarin and apixaban, respectively. Total costs were $94,941 for warfarin and $86,007 for apixaban, demonstrating apixaban to be a dominant economic strategy. Upon one-way sensitivity analysis, these results were sensitive to variability in the drug cost of apixaban and various intracranial hemorrhage related variables. In Monte Carlo simulation, apixaban was a dominant strategy in 57% of 10,000 simulations and cost-effective in 98% at a willingness-to-pay threshold of $50,000 per QALY. In patients with AF and at least one additional risk factor for stroke and a baseline risk of ICH risk of about 0.8%, treatment with apixaban may be a cost-effective alternative to warfarin.

Rivaroxaban has been found to be noninferior to warfarin for preventing stroke or systemic embolism in patients with high-risk atrial fibrillation (AF) and is associated with a lower rate of intracranial hemorrhage. To assess the cost–effectiveness of rivaroxaban compared to adjusted-dose warfarin for the prevention of stroke in patients with AF, we built a Markov model using a United States payer/Medicare perspective and a lifetime time horizon. The base-case analysis assumed a cohort of patients with AF 65 years of age with a congestive heart failure, hypertension, age, diabetes, stroke (2 points) score of 3 and no contraindications to anticoagulation. Data sources included the Rivaroxaban Once-daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) and other studies of anticoagulation. Outcome measurements included costs in 2011 United States dollars, quality-adjusted life years (QALYs), and incremental cost–effectiveness ratios (ICERs). Patients with AF treated with rivaroxaban lived an average of 10.03 QALYs at a lifetime treatment cost of $94,456. Those receiving warfarin lived an average of 9.81 QALYs and incurred costs of $88,544. The ICER for rivaroxaban was $27,498 per QALY. These results were most sensitive to changes in the hazard decrease of intracranial hemorrhage and stroke with rivaroxaban, cost of rivaroxaban, and time horizon. Monte Carlo simulation demonstrated rivaroxaban was cost–effective in 80% and 91% of 10,000 iterations at willingness-to-pay thresholds of $50,000 and $100,000 per QALY, respectively. In conclusion, this Markov model suggests that rivaroxaban therapy may be a cost–effective alternative to adjusted-dose warfarin for stroke prevention in AF.

Physicians are in an ideal position to describe the impact of medication non-medical switching (switching commonly due to formulary changes by insurer for reasons unrelated to patient health) on their practice dynamics and patient care. We sought to examine physicians' openness to requests for non-medical switching and their experiences and opinions regarding the impact of non-medical switching on their practice, staff and patients. An online survey of randomly-sampled physicians spending ≥10% of time providing patient care and having received ≥1 non-medical switch request during the prior 12-months. The impact of non-medical switching on clinical decision-making process; professional experience with clinical practice, patient-physician relationship, insurance process; and perceived impact on practice, staff and patients were assessed. Weighted percent responses were calculated. We sampled 1,010 physicians (response rate = 55.5%). Many responded being frequently not amenable (26.0%) or had reservations (41.8%) to non-medical switch requests; with >50% indicating patient stability on current therapy and suboptimal alternatives as factors frequently influencing amenability. Physicians agreed non-medical switching can create ethical concerns (clinical judgement, autonomy, ability to treat per guidelines; 74.8%, 82.3%, 53.5%, respectively), while forcing them to take responsibility for insurers' decisions (81.1%) and diverting their clinical time (84.3%). Most indicated non-medical switching increased practice burden (administrative, non-billable interactions, additional staffing, non-office patient contact, calls to/from the pharmacy; 85.0%, 72.5%, 62.2%, 64.2%, 69.5%, respectively). Physicians felt insurer processes discouraged non-medical switch challenges (76.7%) and required inconvenient lengths-of-time (76.1%) speaking to insurer representatives without proper expertise (62.0%). They believed non-medical switching negatively impacted aspects of care (effectiveness, side-effects, medication adherence and abandonment, out-of-pocket costs, medication errors; 46.5%, 53.2%, 50.6%, 49.4%, 59.6%, 54.5%, respectively). Physicians were frequently not amenable or had reservations regarding non-medical switching. They noted ethical concerns due to non-medical switching. Most felt non-medical switches burdened their practice and negatively impacted care.

Introduction Obstructive sleep apnea (OSA) is prevalent in patients with venous thromboembolism (VTE). We sought to evaluate the effectiveness and safety of rivaroxaban versus warfarin in VTE patients with comorbid OSA. Methods We performed retrospective cohort analyses using the Optum® de-identified Electronic Health Record data set (Optum® EHR) from November 1, 2011 to June 30, 2023. We included adults with OSA at baseline who newly initiated rivaroxaban or warfarin for an acute VTE and had ≥12 months of prior EHR activity. Patients who had nonvalvular atrial fibrillation, had a hip/knee replacement ≤35 days before the acute VTE, were pregnant, or had active cancer were excluded. Times to recurrent VTE and major bleeding were evaluated. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using propensity score–overlap weighting proportional hazards regression. Results A total of 14,215 patients met the study criteria and were included in the analyses (rivaroxaban: 7453; warfarin: 6762). We observed similar risks of recurrent VTE (HR = 1.0, 95% CI: 0.80-1.26) and major bleeding (HR = 0.87, 95% CI: 0.65-1.17) through 12 months with rivaroxaban- compared to warfarin-treated patients. Conclusion For patients with acute VTE and comorbid OSA, rivaroxaban is as effective as warfarin in preventing recurrent VTE, with a similar risk of major bleeding.

Contemporary data on coccidioidomycosis death rates are sparse. Death certificate data for 2018–2023 from the US National Vital Statistics System were evaluated. Coccidioidomycosis deaths were identified using diagnosis codes B38.x listed anywhere on certificates. Deaths and age-adjusted mortality rates (AAMRs)/1,000,000 people, with 95% confidence intervals (CIs), were determined. We identified 1760 coccidioidomycosis-attributable deaths (AAMR = 0.75; 0.72–0.79). Most occurred in 55–74-year-olds (43.9%; corresponding AAMR = 1.72; 1.59–1.84). Males had a 2.69-fold increased AAMR versus females and American Indian or Alaska Native individuals had a 4.28-fold increased rate versus White individuals. Hispanics had a higher AAMR than the overall population (AAMR = 1.92; 1.76–2.08). AAMRs increased from 0.52 in 2019 to 0.79–0.94 in later years. Most (89.7%) death certificates were from endemic states, with Arizona having the highest AAMR. Seven hundred and thirteen certificates (40.5%) listed coccidioidomycosis as the primary cause of death, with 43.8% coded for pulmonary, 34.9% coded for disseminated, and 21.3% coded for unspecified coccidioidomycosis. Diabetes, COVID-19, and human immunodeficiency virus were more frequent on certificates with coccidioidomycosis versus without (RR range = 1.47–17.20). Mortality remained closely tied to demographic and geographic factors identified in prior studies, with county-level mapping revealing high-burden areas for targeted intervention. Coccidioidomycosis-attributable AAMRs rose over time, possibly influenced by concurrent COVID-19 infection. Only 40% of death certificates listed it as the primary cause, indicating that most patients experience chronic infection rather than death directly from the disease. These findings suggest the need for heightened clinical awareness of coccidioidomycosis, along with earlier diagnosis and prompt initiation of antifungal treatment in these high-risk groups.

While we acknowledge that some (not all) guidelines recommend 50 U/kg, this recommendation is based upon limited data and neither dose has been assessed in clinical trials and been proven safe or efficacious or is approved by authorities for this indication. Prior studies comparing low- and high-dose 4F-PCC for reversal of oral FXai have demonstrated 25 U/kg is used more frequently in routine practice, and neither hemostatic effectiveness nor in-hospital mortality appear to be superior with the 50 U/kg dose versus 25 U/kg [3, 4]. While our propensity score-weighted comparative study design is not a substitute for a head-to-head randomized comparison, until the completion of ANNEXA-I we maintain this indirect comparison provides additional information to support clinicians in making treatment decisions.