Reversing factor Xa inhibitors - clinical utility of andexanet alfa

Approximately half of patients started on an oral anticoagulant in the USA now receive one of the newer direct oral anticoagulants (DOACs). Although there is an approved reversal agent for the direct thrombin inhibitor dabigatran, a specific reversal agent for the anti-factor Xa (FXa) DOACs has yet to be licensed. Unlike the strategy to reverse the only oral direct thrombin inhibitor with idarucizumab, which is a humanized monoclonal antibody fragment, a different approach is necessary to design a single agent that can reverse multiple anti-FXa medications. Andexanet alfa is a FXa decoy designed to reverse all anticoagulants that act through this part of the coagulation cascade including anti-FXa DOACs, such as apixaban, edoxaban and rivaroxaban, and indirect FXa inhibitors such as low-molecular-weight heparins. This narrative reviews the development of andexanet alfa and explores its basic science, pharmacokinetics/pharmacodynamics, animal models, and human studies

Trends in Venous Thromboembolism Anticoagulation in Patients Hospitalized With COVID-19

Importance: Venous thromboembolism (VTE) is a common complication of COVID-19. It is not well understood how hospitals have managed VTE prevention and the effect of prevention strategies on mortality. Objective: To characterize frequency, variation across hospitals, and change over time in VTE prophylaxis and treatment-dose anticoagulation in patients hospitalized for COVID-19, as well as the association of anticoagulation strategies with in-hospital and 60-day mortality. Design, Setting, and Participants: This cohort study of adults hospitalized with COVID-19 used a pseudorandom sample from 30 US hospitals in the state of Michigan participating in a collaborative quality initiative. Data analyzed were from patients hospitalized between March 7, 2020, and June 17, 2020. Data were analyzed through March 2021. Exposures: Nonadherence to VTE prophylaxis (defined as missing ≥2 days of VTE prophylaxis) and receipt of treatment-dose or prophylactic-dose anticoagulants vs no anticoagulation during hospitalization. Main Outcomes and Measures: The effect of nonadherence and anticoagulation strategies on in-hospital and 60-day mortality was assessed using multinomial logit models with inverse probability of treatment weighting. Results: Of a total 1351 patients with COVID-19 included (median [IQR] age, 64 [52-75] years; 47.7% women, 48.9% Black patients), only 18 (1.3%) had a confirmed VTE, and 219 (16.2%) received treatment-dose anticoagulation. Use of treatment-dose anticoagulation without imaging ranged from 0% to 29% across hospitals and increased over time (adjusted odds ratio [aOR], 1.46; 95% CI, 1.31-1.61 per week). Of 1127 patients who ever received anticoagulation, 392 (34.8%) missed 2 or more days of prophylaxis. Missed prophylaxis varied from 11% to 61% across hospitals and decreased markedly over time (aOR, 0.89; 95% CI, 0.82-0.97 per week). VTE nonadherence was associated with higher 60-day (adjusted hazard ratio [aHR], 1.31; 95% CI, 1.03-1.67) but not in-hospital mortality (aHR, 0.97; 95% CI, 0.91-1.03). Receiving any dose of anticoagulation (vs no anticoagulation) was associated with lower in-hospital mortality (only prophylactic dose: aHR, 0.36; 95% CI, 0.26-0.52; any treatment dose: aHR, 0.38; 95% CI, 0.25-0.58). However, only the prophylactic dose of anticoagulation remained associated with lower mortality at 60 days (prophylactic dose: aHR, 0.71; 95% CI, 0.51-0.90; treatment dose: aHR, 0.92; 95% CI, 0.63-1.35). Conclusions and Relevance: This large, multicenter cohort of patients hospitalized with COVID-19, found evidence of rapid dissemination and implementation of anticoagulation strategies, including use of treatment-dose anticoagulation. As only prophylactic-dose anticoagulation was associated with lower 60-day mortality, prophylactic dosing strategies may be optimal for patients hospitalized with COVID-19

Cryptococcal eosinophilic meningitis in a patient with sarcoidosis

A 51-year-old African-American man with underlying pulmonary, hepatic and splenic sarcoidosis, reported a 3-day history of headache, neck stiffness and photophobia. He was not using medication for chronic sarcoidosis. Physical examination was significant for nuchal rigidity. Lumbar puncture revealed marked eosinophilia in the cerebrospinal fluid, which, on further analysis, demonstrated a positive cryptococcal antigen. HIV antibody and PCR tests were negative. Bronchoscopy and fungal blood cultures were also negative. The patient was started on amphotericin B and flucytosine, with significant clinical improvement. He recovered well without any neurological sequelae and remained symptom-free at 2-week follow-up. Cryptococcal central nervous infections are uniformly fatal if left untreated. Prompt diagnosis and treatment is essential, to prevent the associated high morbidity and mortality

Management of Elective Surgery and Emergent Bleeding with Direct Oral Anticoagulants.

PURPOSE OF REVIEW: The purpose of this review was to offer practical management strategies for when patients receiving direct oral anticoagulants require elective surgery or present with bleeding complications. RECENT FINDINGS: Clinical practice guidelines are now available on the timing of periprocedural interruption of treatment with the newer direct oral anticoagulants based on their pharmacodynamics and pharmacokinetics and based on findings from cohort studies and clinical trials. An antibody that reverses the effects of dabigatran is now available, and a factor Xa decoy is being developed as an antidote to apixaban, betrixaban, edoxaban, and rivaroxaban. The timing of interruption of direct oral anticoagulants for elective surgery is based on multiple factors, including pharmacologic properties and interactions, the patient\u27s renal function, and the type of planned surgery. There is little role for low-molecular-weight heparin bridging. Idarucizumab is the treatment of choice for dabigatran-related life-threatening bleeding, while andexanet alfa is being developed to reverse factor Xa inhibitors

Michigan risk score to predict picc-related venous thromboembolism

Background: Peripherally inserted central catheters (PICCs) have been associated with venous thromboembolism (VTE) and are a major cause of upper xtremity deep vein thrombosis (DVT). However, mechanisms to identify patients at greatest risk of PICC-associated VTE are limited. Methods: Using data from the Michigan Hospital Medicine Safety consortium, patients with PICCs that experienced symptomatic, image-confirmed upper-extremity DVT were identified. A logistic, mixed effect, two-stage model with hospital-specific random intercepts was used to identify factors associated with PICC-DVT. Points were assigned to each predictor, stratifying patients into four classes for risk of PICC-DVT. Validation was performed by internal bootstrapping with results expressed as odds ratios (OR) and 95% confidence intervals (CI).Results: Of 22,056 patients that received PICCs, 478 (2.2%) developed symptomatic PICC-DVT were included in the analysis. Risk factors associated with PICC-DVT following two-stage modeling included: history of DVT; use of a multi-lumen PICC; active cancer; presence of another CVC when the PICC was placed; and a white blood cell count greater than 12,000 at the time of PICC insertion (Table 1). Thrombosis rates were 0.8% for class I, 1.7% for class II, 2.9% for class III and 6.9% for class IV. The risk classification rule was significantly associated with VTE risk (p\u3c0.0001), with ORs of PICC-DVT of 1.83 (95 % CI: 1.30, 2.57), 3.30 (95 % CI: 2.43, 4.49) and 8.27 (95 % CI: 5.69, 12.01) for risk classes II, III and IV vs. risk class I, respectively (Table 2). The area under the receiver-operating-characteristics curve was 0.72, with an estimated optimism of 0.02 from the bootstrap internal validation data, suggesting excellent performance. Conclusions: The Michigan Risk Score offers a novel way to predict and categorize risk of PICC-VTE and advances the field in several ways. First, it can help identify patients at high-risk of thrombosis when considering PICC placement. Second, the tool may help inform surveillance or testing among those at high-risk in the setting of vague symptoms. Finally, the risk score could also help inform duration of anticoagulation in patients with PICC-associated thrombosis, with consideration of extended courses in those at highest risk of this event. External validation of this rule with studies that explore implementation in real-world practice are needed

Management of Elective Surgery and Emergent Bleeding with Direct Oral Anticoagulants

PURPOSE OF REVIEW: The purpose of this review was to offer practical management strategies for when patients receiving direct oral anticoagulants require elective surgery or present with bleeding complications. RECENT FINDINGS: Clinical practice guidelines are now available on the timing of periprocedural interruption of treatment with the newer direct oral anticoagulants based on their pharmacodynamics and pharmacokinetics and based on findings from cohort studies and clinical trials. An antibody that reverses the effects of dabigatran is now available, and a factor Xa decoy is being developed as an antidote to apixaban, betrixaban, edoxaban, and rivaroxaban. The timing of interruption of direct oral anticoagulants for elective surgery is based on multiple factors, including pharmacologic properties and interactions, the patient\u27s renal function, and the type of planned surgery. There is little role for low-molecular-weight heparin bridging. Idarucizumab is the treatment of choice for dabigatran-related life-threatening bleeding, while andexanet alfa is being developed to reverse factor Xa inhibitors

Patterns and Predictors of Short-Term Peripherally Inserted Central Catheter Use: A Multicenter Prospective Cohort Study.

BACKGROUND: The guidelines for peripherally inserted central catheters (PICCs) recommend avoiding insertion if the anticipated duration of use is =5 days. However, short-term PICC use is common in hospitals. We sought to identify patient, provider, and device characteristics and the clinical outcomes associated with short-term PICCs. METHODS: Between January 2014 and June 2016, trained abstractors at 52 Michigan Hospital Medicine Safety (HMS) Consortium sites collected data from medical records of adults that received PICCs during hospitalization. Patients were prospectively followed until PICC removal, death, or 70 days after insertion. Multivariable logistic regression models were fit to identify factors associated with short-term PICCs, defined as dwell time of =5 days. Complications associated with short-term use, including major (eg, venous thromboembolism [VTE] or central lineassociated bloodstream infection [CLABSI]) or minor (eg, catheter occlusion, tip migration) events were assessed. RESULTS: Of the 15,397 PICCs placed, 3902 (25.3%) had a dwell time of =5 days. Most (95.5%) short-term PICCs were removed during hospitalization. Compared to PICCs placed for \u3e5 days, variables associated with short-term PICCs included difficult venous access (odds ratio [OR], 1.54; 95% confidence interval [CI], 1.40-1.69), multilumen devices (OR, 1.53; 95% CI, 1.39-1.69), and teaching hospitals (OR, 1.25; 95% CI, 1.04-1.52). Among those with short-term PICCs, 374 (9.6%) experienced a complication, including 99 (2.5%) experiencing VTE and 17 (0.4%) experiencing CLABSI events. The most common minor complications were catheter occlusion (4%) and tip migration (2.2%). CONCLUSION: Short-term use of PICCs is common and associated with patient, provider, and device factors. As PICC placement, even for brief periods, is associated with complications, efforts targeted at factors underlying such use appear necessary