David Paje

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.

The Michigan Risk Score to predict peripherally inserted central catheter-associated thrombosis

Essentials How best to quantify thrombosis risk with peripherally inserted central catheters (PICC) is unknown. Data from a registry were used to develop the Michigan Risk Score (MRS) for PICC thrombosis. Five risk factors were associated with PICC thrombosis and used to develop a risk score. MRS was predictive of the risk of PICC thrombosis and can be useful in clinical practice.

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 line‐associated 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 >5 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.

Current Trends in Anticoagulation Bridging for Patients With Chronic Atrial Fibrillation on Warfarin Undergoing Endoscopy

For warfarin-treated patients with atrial fibrillation (AF) at low thromboembolic risk, recent studies have shown harm associated with periprocedural bridging using low-molecular-weight heparin. Clinician surveys have indicated a preference toward excessive bridging, especially among noncardiologists; however, little is known about actual practice patterns in these patients. We performed a retrospective evaluation of bridging in the setting of gastrointestinal endoscopy. We identified 938 patients with AF on warfarin who underwent esophagogastroduodenoscopy or colonoscopy between 2012 and 2016 at a tertiary health center. Urgent, inpatient, or advanced endoscopic procedures were excluded. Clinical variables were abstracted using a predefined data dictionary. Values were expressed as means and compared using a t test or a chi-squared test as appropriate. Three hundred seventy-four patients met criteria for analysis. Twenty-five percent of these patients received bridging therapy, including 11% of patients with CHADS2 scores of 0 to 2 without valvular AF or previous venous thromboembolism. Of the clinical variables assessed, CHADS2, CHA2DS2-VASc, and a history of stroke were the strongest predictors of bridging. Cardiologists were also significantly less likely to prescribe bridging than noncardiology providers (18% vs 30%, p = 0.011); this effect was significant when controlling for CHADS2, CHA2DS2-VASc, or stroke history. In conclusion, patients with AF on warfarin receive excessive low-molecular-weight heparin bridging in the setting of endoscopy; the lower rates of bridging observed among cardiologists suggests a need for their increased involvement in this decision making.

Variation in use of technology among vascular access specialists: an analysis of the PICC1 survey

Background While the use of technologies such as ultrasound and electrocardiographic (ECG) guidance systems to place peripherally inserted central catheters (PICCs) has grown, little is known about the clinicians who use these tools or their work settings. Methods Using data from a national survey of vascular access specialists, we identified technology users as PICC inserters that: (a) use ultrasound to find a suitable vein for catheter placement; (b) measure catheter-to-vein ratio; and (c) use ECG for PICC placement. Individual and organizational-level characteristics between technology users versus non-users were assessed. Bivariable comparisons were made using Chi-squared or Fishers exact tests; two-sided alpha with p<0.05 was considered statistically significant. Results Of the 2762 PICC inserters who accessed the survey, 1518 (55%) provided information regarding technology use. Technology users reported greater experience than non-technology users, with a higher percentage stating they had placed >1000 PICCs (55% vs. 45%, p<0.001). A significantly greater percentage of technology users also reported being certified in vascular access by an external agency than non-technology users (75% vs. 63%, p<0.001). Technology users were more often part of vascular access teams with ≥10 members compared to non-technology users (35% vs. 22%, p<0.001). Some practices also varied between the two groups: for example, use of certain securement devices and dressings differed between technology users and non-users (p<0.001). Conclusions Technology use by vascular access clinicians while placing PICCs is associated with clinician characteristics, work setting and practice factors. Understanding whether such differences influence clinical care or patient outcomes appears necessary.

Management of Elective Surgery and Emergent Bleeding with Direct Oral Anticoagulants

Purpose of ReviewThe 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 FindingsClinical 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.SummaryThe timing of interruption of direct oral anticoagulants for elective surgery is based on multiple factors, including pharmacologic properties and interactions, the patient’s 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.

Annals for Hospitalists Inpatient Notes - Oral Anticoagulation for the Hospitalist—Expanded Choices Improve Patient-Centered Care

Initiation of anticoagulant medications is among the most common and critical tasks hospitalists perform. Appropriate anticoagulation entails thoughtful consideration of individual circumstances, including the competing risks for thrombosis and bleeding. For more than half a century, vitamin K antagonists (VKAs), such as warfarin, were the only oral agents available for long-term anticoagulation. Their serendipitous discovery from plant products predated the recognition of vitamin K itself and the understanding of its role in coagulation. It took decades to fully realize the therapeutic potential of VKAs. It was not until the late 1990s that standardized protocols and nomograms along with involvement of nurse- or pharmacist-run anticoagulation clinics enabled physicians to optimize their efficacy and safety. However, up to half of all patients are still unable to maintain adequate anticoagulation control with VKAs because of their narrow therapeutic window and multiple drug and food interactions. In the past decade, novel agentscollectively known as direct-acting oral anticoagulants (DOACs)have emerged (1). The development of these agents was deliberate, using rational design approaches involving small molecules that target specific proteins in the coagulation cascade. Dabigatran directly inhibits thrombin, whereas rivaroxaban, apixaban, and edoxaban act against factor Xa. These agents offer substantial patient-oriented advantages, such as rapid onset and cessation of action as well as more predictable pharmacokinetics, which allows for simple fixed once- or twice-daily dosing without the frequent blood monitoring or dose adjustments necessary with VKAs. With increasing clinical experience and data on their efficacy and safety, DOACs have quickly become the drugs of choice for the most common oral anticoagulation indications. Among patients with nonvalvular atrial fibrillation, these drugs are associated with fewer strokes and systemic emboli, less intracranial hemorrhage, and a similar incidence of major bleeding compared with warfarin (2). In noncancer-related venous thromboembolism (VTE), DOACs are as efficacious as VKAs in preventing recurrent VTE and death and cause less intracranial, fatal, and clinically relevant nonmajor bleeding (3). Although many clinicians predicted the extinction of warfarin once the DOACs were introduced, such predictions have not come true. Instead, the use of warfarin remains common, particularly among patients who cannot be safely treated with a DOAC, such as those with mechanical heart valves or severe renal insufficiency (4). Also, clinical efficacy data for DOACs are lacking in certain populations, such as those with cancer-associated VTE or severe thrombophilias, therefore limiting use in these patients. Perhaps most important, the high out-of-pocket cost of DOACs makes them unaffordable for many patients with inadequate prescription coverage. For these reasons, warfarin remains the anticoagulant of choice for many patients. Hospitalists must now assess both the necessity of oral anticoagulant therapy and the selection of an appropriate agent as they formulate strategies to maximize efficacy and reduce potential complications. The added burden of choosing the right anticoagulant drug and identifying the optimal dose can be reduced by partnering with robust anticoagulation clinics (5). The nurses and pharmacists staffing these clinics have long provided the necessary expertise and highest quality of care to warfarin-treated patients through education and laboratory monitoring and by ensuring long-term adherence. The same support can (and should) be provided to DOAC-treated patients, who will benefit from education about bleeding prevention and management, renal function monitoring, and ensuring medication adherence. The anticoagulation clinic can also assist in weighing the bleeding and thrombotic risks of surgical procedures and recommend optimal perioperative management strategies. The expanded choices for oral anticoagulation offer an opportunity to engage patients in shared decision-making discussions. In the past, patients were offered only warfarin to treat or prevent blood clots. Now, they can discuss with their physicians the benefits and drawbacks of up to 5 different agents to determine which best fits their clinical circumstances, lifestyle, and finances. Patient engagement in this critical decision making holds hope for improved adherence, which is especially important in cases of nonvalvular atrial fibrillation because historically up to half of these patients discontinue anticoagulant therapy within 1 year. Some clinicians predict that warfarin use will eventually decline with the introduction of DOAC-specific reversal agents. However, we believe that warfarin will remain an important anticoagulant for selected populations. Clopidogrel has persisted despite the introduction of prasugrel and ticagrelorso, too, will warfarin. And because the initial selection of anticoagulants often occurs in the hospital, hospitalists must be prepared to assist patients in choosing from a broader selection of oral anticoagulants based on their individual specific clinical and personal circumstances.