Comparison of Managing Factor Xa Inhibitor to Unfractionated Heparin Transitions by aPTT Versus a Treatment Guideline Utilizing Heparin Anti-Xa Levels.

BACKGROUND: There are inadequate data on the optimal strategy for transitioning factor Xa inhibitors (FXai; apixaban, rivaroxaban) to unfractionated heparin (UFH) infusions. OBJECTIVE: In patients transitioning from an FXai to an UFH infusion, this study compared the safety and efficacy of monitoring UFH infusions using an activated partial thromboplastin time (aPTT) titration scale versus utilizing an UFH-calibrated anti-Xa titration scale aided by a novel institutional guideline. METHODS: A retrospective cohort analysis was conducted on adult patients transitioning from an FXai to an UFH infusion at 2 medical centers from June 1, 2018, to November 1, 2020. One institution utilized aPTT while the other institution primarily used UFH-calibrated anti-Xa. The primary endpoint was a composite of death, major bleeding, or new thrombosis during the hospitalization with a planned noninferiority analysis. Secondary outcomes were also collected including the amount and duration of UFH administered between cohorts. RESULTS: The incidence rate of the primary composite endpoint was 6.3% in the anti-Xa group and 11% in the aPTT group (P < 0.001 for noninferiority, P = 0.138 for superiority) meeting noninferiority criteria. No statistical differences were seen in new thrombosis, major bleeding, or any bleeding. CONCLUSION AND RELEVANCE: This represents the first report of a comparison between aPTT versus anti-Xa monitoring in relation to clinical outcomes for patients transitioning from an FXai to an UFH infusion. A transition guideline primarily utilizing an UFH-calibrated anti-Xa assay appears to be a safe alternative to aPTT monitoring and can aid facilities in the management of patients during these complex transitions.

Transitioning hospitalized patients from rivaroxaban or apixaban to a continuous unfractionated heparin infusion: A retrospective review.

PURPOSE: To determine a patient's clinical course based on the use of an activated partial thromboplastin time (aPTT) or heparin anti-Xa assay when transitioning from rivaroxaban or apixaban to an unfractionated heparin infusion. METHODS: A retrospective chart review was conducted to investigate how unfractionated heparin infusions were managed at a tertiary care hospital in the setting of recent apixaban or rivaroxaban administration. Patients were separated into 2 cohorts based on the chosen heparin infusion monitoring assay: heparin anti-Xa or aPTT. The primary composite outcome was total number of bleeding and thrombotic events; the secondary composite outcome was average incidence of heparin infusion holds and rate changes per patient. RESULTS: Data were collected from 76 patients (heparin anti-Xa = 69, aPTT = 7). Due to the limited number of patients within the aPTT cohort, this data was excluded from the analysis, and heparin anti-Xa descriptive statistics were reported without statistical comparisons. In the heparin anti-Xa group, a total of 10 bleeds and 1 thrombus were discovered. Additionally, the average number of infusion holds and rate changes was 0.841 and 2.65 times per patient, respectively, for those patients monitored via heparin anti-Xa assay. CONCLUSION: In the presence of a recently administered oral anti-Xa anticoagulant, more down-titrations occurred in the initial 6 hours of the heparin infusion when measuring anti-Xa activity, and most up-titrations occurred after 36 hours. Baseline heparin anti-Xa activity may be a useful tool to identify patients with residual plasma concentrations of apixaban and rivaroxaban to help better individualize heparin therapy.

Current Strategies for the Management of Bleeding Associated with Direct Oral Anticoagulants and a Review of Investigational Reversal Agents.

BACKGROUND: The management of life-threatening bleeding in patients who are receiving direct oral anticoagulants (DOACs) is a serious medical concern. OBJECTIVE: This review provides a concise, balanced overview of the current and future approaches for reversing the anticoagulation effects of DOACs, particularly factor Xa (FXa) inhibitors. DISCUSSION: The anticoagulant activity of the direct thrombin inhibitor dabigatran can be reversed by idarucizumab, but until recently, options for the management of major bleeding in patients who were receiving FXa inhibitors were limited to nonspecific strategies, including supplementation of clotting factors with prothrombin complex concentrates (PCCs) or activated PCCs for attenuating anticoagulation effects. They appear as a treatment option in many hospital guidelines despite the lack of approval by the U.S. Food and Drug Administration and the lack of rigorous medical evidence supporting their use in this setting. The development of specific reversal agents may provide improved strategies for the management of bleeding. Andexanet alfa is a modified FXa molecule approved in the United States to reverse the anticoagulant effects of FXa inhibitors (rivaroxaban and apixaban) in patients with life-threatening or uncontrolled bleeding. Ciraparantag is a small-molecule inhibitor of multiple anticoagulants that has been investigated in healthy subjects. CONCLUSION: The current guidelines for management of DOAC-associated bleeding are being updated to reflect that the reversal agent for rivaroxaban and apixaban is now available. For other FXa inhibitors, in the absence of a reversal agent, nonspecific strategies that include PCCs are recommended. The population of patients anticoagulated with DOACs is growing, and we hope that specific reversal agents will improve the approach to management of major bleeding in this population.

Use of Direct Oral Anticoagulants in Morbidly Obese Patients.

In 2016, the International Society on Thrombosis and Haemostasis (ISTH) published guidelines advising caution when using direct oral anticoagulants (DOACs) in patients with morbid obesity due to limited clinical efficacy and safety data supporting their use in this patient population. In this review, we analyzed published articles in the MEDLINE database (from inception through May 29, 2019), and the Cochrane Library, Google Scholar, and EMBASE databases (from inception through April 26, 2019) that evaluated morbidly obese patients with atrial fibrillation (AF) or venous thromboembolism (VTE) who received DOACs. A total of 19 studies, which included pharmacokinetic studies, original phase III trials for the DOACs, post hoc analyses of phase III trials, and retrospective cohort studies, were evaluated. Although currently available data do not indicate that using DOACs in the morbidly obese is problematic, DOAC-specific pharmacokinetic variations have been observed. Additionally, less data evaluating DOAC efficacy and safety exist for VTE treatment compared with the data for stroke prevention in patients with AF. The overall quality of the studies included in this review was low due to limited prospective randomized trial data, limiting the ability to form definitive judgments on efficacy and safety DOACs in the morbidly obese. Continued caution is recommended when considering DOAC use in the morbidly obese, particularly for those requiring anticoagulation for VTE treatment, until additional higher-quality data become available.

Use of specific anti-Xa levels in acute kidney injury to transition patients from oral factor Xa inhibitors to i.v. heparin infusion.

PURPOSE: This case series presents 3 patients with acute kidney injury taking apixaban or rivaroxaban and transitioning to a heparin infusion. SUMMARY: Case 1 was a 78-year-old man admitted with respiratory failure, acute decompensated heart failure, and acute kidney injury. He was taking apixaban for atrial flutter. He was transitioned to an i.v. heparin infusion and had 2 consecutive heparin antifactor-Xa levels greater than 2 units/mL. Heparin was held and resumed about 36 hours later when the apixaban anti-Xa level was less than 50 ng/mL. Case 2 was a 55-year-old man admitted with acute kidney injury, taking apixaban for a recent deep vein thrombosis. Apixaban anti-Xa levels were monitored and i.v. heparin was initiated when the level was less than 100 ng/mL, about 56 hours after the last apixaban dose. Case 3 was a 64-year-old woman admitted with sepsis and acute kidney injury taking rivaroxaban for pulmonary embolism, which occurred 2 weeks prior to admission. Rivaroxaban anti-Xa levels were monitored and i.v. heparin was initiated about 36 hours after the last dose when the level was less than 100 ng/mL. The management strategy did not lead to any thrombotic outcomes; however, 1 patient experienced bleeding. CONCLUSION: Specific anti-Xa levels for rivaroxaban and apixaban appeared to be helpful in the transition of 3 patients to unfractionated heparin infusions in the setting of acute kidney injury. These levels provided enhanced, individualized care and likely helped avoid over and under anticoagulation.

Successful use of laboratory monitoring to facilitate an invasive procedure for a patient treated with dabigatran.

PURPOSE: A case in which novel and traditional laboratory markers were successfully used to determine surgical intervention timing in an elderly patient receiving dabigatran for atrial fibrillation is reported. SUMMARY: An 86-year-old woman who was taking dabigatran for atrial fibrillation suffered a right femoral neck fracture requiring surgical intervention. Dabigatran was withheld once the patient was admitted to the hospital, and the pharmacy inpatient anticoagulation management team was consulted for guidance on determining appropriate scheduling of surgical intervention with regard to the time since her most recent dabigatran dose to minimize bleeding complications. The team recommended delaying surgery, as dabigatran clearance would likely take 3-5 days and an ecarin chromogenic assay (ECA) dabigatran value of <50 ng/mL would be desirable before surgical intervention. During her hospitalization, novel and traditional laboratory markers for dabigatran, such as ECA value, activated partial thromboplastin time, thrombin time, and prothrombin time, were measured and followed closely to determine the best time to perform surgical intervention to minimize bleeding risk. Renal dysfunction likely delayed dabigatran elimination in the patient and may have led to potential accumulation of dabigatran. The patient ultimately had to wait 5 days after the last dabigatran dose for surgical intervention. CONCLUSION: Coagulation assay monitoring for dabigatran, with emphasis on an ECA dabigatran concentration of <50 ng/mL, was used to assess safety regarding bleeding risk before a nonemergent surgical procedure in an 86-year-old woman with a right femoral neck fracture.

Overview of direct oral anticoagulant therapy reversal.

PURPOSE: Strategies for the management of bleeding complications and facilitation of an invasive procedure in patients receiving direct oral anticoagulants (DOACs) are reviewed. SUMMARY: The DOACs provide clinical advantages versus vitamin K antagonists, including fixed dosing with no routine coagulation monitoring and evidence of a lower risk of bleeding. However, as with all anticoagulants, there is a risk of bleeding complications in patients receiving DOACs, so urgent reversal of their anticoagulant activity may be required for spontaneous or traumatic bleeding events and in patients undergoing emergency invasive procedures. Reversal strategies are dependent on the anticoagulant involved, the location and severity of the bleeding, and/or the urgency of the invasive procedure. The recently approved specific reversal agent for dabigatran, idarucizumab, together with other reversal agents in development will hopefully allow for the emergent reversal of DOACs, without increasing the underlying risk of thrombosis. However, research is required to determine the optimal use of these reversal agents, in terms of choice of agent, dosing, and concomitant management. A systematic approach to their implementation in hospitals is also required to ensure that physicians, nurses, and pharmacists receive appropriate education and have the necessary protocols and guidelines to manage these clinical situations. CONCLUSION: Reversal strategies in patients receiving a DOAC need to be tailored to the anticoagulant involved as well as the urgency and severity of the clinical situation. Reversal agents should help facilitate the urgent reversal of anticoagulation in patients with emergency bleeding or who require urgent surgery, though research and education are required to ensure the optimal use of these agents.

Relationship between time spent at extreme International Normalized Ratios and time in therapeutic range with bleeding and thrombosis in warfarin-treated patients.

PURPOSE: The relationship between the time spent at extreme International Normalized Ratios (INRs) and the time in the therapeutic range (TTR) with bleeding and thrombosis in warfarin-treated patients was examined. METHODS: Consecutive patients treated with warfarin for atrial fibrillation or for venous thrombosis who were managed by the anticoagulation management service or adult internal medicine clinic of a large, tertiary care, integrated health system between June 1, 2011, and October 9, 2012, were eligible for study inclusion. Data collected for the outcomes analysis included INRs and dates; current use of aspirin, clopidogrel, prasugrel, ticagrelor, ticlopidine, or nonsteroidal antiinflammatory drugs; and any clinically significant bleeding or thrombosis events identified. RESULTS: In the 837 patients who met the inclusion criteria, 636.5 patient-years of therapy were provided, of which 14.4 patient-years (2.26% of time) were spent at INRs of <1.5; 2.9 patient-years of therapy (0.45% of time) were spent at INRs of >4.5. The patient population had a mean individual TTR of 65%. The percentage of time at an INR of >4.5 was positively associated with an increased risk of major bleeding (p = 0.0085). The percentage of time spent with an INR of <1.5 was not associated with a significant increase in the risk of thrombosis. CONCLUSION: The percentage of time spent with an INR of >4.5 was associated with an increased risk of major bleeding in patients receiving warfarin for atrial fibrillation or for venous thrombosis at two outpatient clinics. The relationships between thrombosis risk and the TTR or the time spent at an INR of <1.5 were not significant, but the thromboembolic event rate was unusually low, as was the time spent at an INR of <1.5.

Rivaroxaban: practical considerations for ensuring safety and efficacy.

Rivaroxaban is the first agent available within a new class of anticoagulants called direct factor Xa inhibitors. Rivaroxaban is approved for use in the United States for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, for the prevention of deep vein thrombosis in patients undergoing total hip replacement and total knee replacement, for the treatment of deep vein thrombosis and pulmonary embolism, and for the reduction in risk of recurrence of deep vein thrombosis and pulmonary embolism (with additional indications under review). Rivaroxaban dose and frequency of administration vary depending on the indication. As of result of predictable pharmacokinetics and pharmacodynamics, a fixed dose of rivaroxaban is administered without routine coagulation testing. Rivaroxaban has a short half-life, undergoes a dual mode of elimination (hepatic and renal), and is a substrate for P-glycoprotein. Rivaroxaban has a lower potential for drug interactions compared with warfarin. Despite the advantages of a once/day fixed-dose oral agent, in many clinical situations limited evidence is available to guide optimal management of rivaroxaban therapy. In this article, we review the available evidence and provide recommendations where possible for such situations including the desire to monitor the anticoagulation intensity, use in special patient populations, managing drug interactions, and transitioning across anticoagulant agents. Potential strategies for reversing rivaroxaban's anticoagulant effect are reviewed. Health systems will need to perform a systematic safety evaluation and ensure that numerous hospital policies related to anticoagulation are updated to include rivaroxaban. A comprehensive approach to education is needed for clinicians, patients, and technical support personnel involved in patient interactions to ensure safe use.

High-dose argatroban for treatment of heparin-induced thrombocytopenia with thrombosis: a case report and review of laboratory considerations.

PURPOSE: A case report describing high-dose argatroban for the treatment of heparin-induced thrombocytopenia (HIT) with thrombosis and associated considerations in interpreting laboratory monitoring data are presented. SUMMARY: A 51-year-old woman with an extensive history of coronary artery disease arrived at the emergency department with complaints of chest pain. The patient was admitted, and coronary artery bypass graft surgery was ultimately performed. The patient had a baseline platelet count of 177,000 cells/µL. During hospitalization, the patient received heparin, and her platelet count dropped to 12,000 cells/µL 13 days after the initiation of heparin. The patient developed swelling around a peripherally inserted central catheter and later developed deep vein thrombosis. An argatroban infusion of 2 µg/kg/min was initiated, with a target activated partial thromboplastin time (aPTT) of 40-80 seconds. After 5 days of therapy, the patient had increased swelling in her right arm and an aPTT of 56 seconds. Her goal aPTT was subsequently increased. Six days later, the patient developed a left-lower-extremity DVT despite aPTTs within the goal range. A new aPTT target of >75 seconds was set. The infusion rate was increased to 15.5 µg/kg/min to attain the target aPTT. Results of an in vitro test led to an alternative interpretation of aPTT and International Normalized Ratio values that aided in the monitoring of argatroban during the high-dose infusion. CONCLUSION: A patient with HIT with thrombosis was successfully treated with unusually high dosages of argatroban and may have had serum argatroban concentrations exceeding what has commonly been thought to be the therapeutic range.

Inpatient warfarin: experience with a pharmacist-led anticoagulation management service in a tertiary care medical center.

PURPOSE: The implementation of a pharmacist-led anticoagulation management service (AMS) and the clinical outcomes of inpatients receiving warfarin management are described. SUMMARY: An AMS was established at St. Mary's Medical Center (SMMC) in Duluth, Minnesota, in November 2003 at the request of orthopedic surgeons to manage warfarin for their patients postoperatively. The AMS was also available to other inpatients by physician request. All AMS pharmacists received didactic and experiential training. Each day, the managing pharmacist, usually the decentralized pharmacist, was responsible for checking the patients' International Normalized Ratio (INR); reviewing other pertinent laboratory test values, any medication changes, and vital signs; monitoring changes in the patients' clinical status, and writing an order for a warfarin dose. A database was created to help monitor patients managed by the AMS and to analyze monthly outcomes data. Clinical outcomes data were evaluated to identify areas of improvement for the AMS. All hospitalizations for patients who received anticoagulation therapy with warfarin managed by the AMS from January 1, 2006, through August 31, 2007, were analyzed. Primary endpoints, including thrombosis and bleeding complications during hospitalization, were identified for inclusion in the final hospital discharge data. Of the 2794 hospitalizations for patients managed by the AMS evaluated, 59 complications were identified. Of these, 14 (0.5%) were thrombosis events and 45 (1.6%) were bleeding events. INR results were also analyzed as secondary endpoints. CONCLUSION: The evaluation of outcomes of the inpatient-based AMS at SMMC provided critical information to the anticoagulation subcommittee for consideration of quality-improvement efforts.

Dabigatran etexilate in clinical practice: confronting challenges to improve safety and effectiveness.

A number of novel anticoagulants are moving through various stages of drug development. Recently, the United States Food and Drug Administration approved the oral direct thrombin inhibitor dabigatran etexilate to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Although dabigatran offers a number of advantages over existing oral and parenteral anticoagulants, challenges exist for clinicians who must ensure its safe and effective use. Limited data are available on dabigatran use in patients with renal dysfunction and in obese patients, or in combination with other drugs. Clinical experience is lacking in populations for whom anticoagulants are routinely used, such as patients with a previous stroke, acute coronary syndromes, or pregnancy-associated thrombosis, or those requiring ablation therapy. More important, clinicians will be faced with incorporating dabigatran into hospital guidelines for transitioning between oral and parenteral anticoagulants, measuring anticoagulant intensity, managing anticoagulant-related hemorrhage, ensuring safe use around neuraxial anesthesia, and implementing computer-based alert or warning systems. Since anticoagulants are ubiquitously used in the prevention or treatment of venous and arterial thrombosis, both clinicians and patients must be provided structured education on dabigatran's benefits and limitations. In this article, our goal was to provide practical advice to enhance clinician understanding of dabigatran, identify clinical and operational challenges to its use, and offer system improvements that can ensure safe and effective use of dabigatran.

Key articles and guidelines in the treatment of venous thromboembolism.

Venous thromboembolism (VTE) is a significant medical diagnosis that affects millions of patients each year. Appropriate management of VTE can help treat the initial event as well as reduce the frequency of complications such as postthrombotic syndrome, pulmonary hypertension, and death. Due to increasing regulatory requirements, hospitals nationwide are developing necessary documentation of appropriate and safe use of anticoagulants for the management of VTE. It is essential that a wide range of clinicians have an understanding of what constitutes appropriate VTE treatment in various patient populations. With the existence of numerous pharmacologic agents, abundance of major clinical trials, and nationally recognized clinical guidelines, compiling the needed reference material to make evidence-based decisions on appropriate VTE treatment can be difficult for clinicians. Therefore we have provided bibliographies of key articles and guidelines related to the treatment of VTE with a number of different strategies in a variety of special patient populations. It is our hope that this compilation will serve as a resource for pharmacists, physicians, nurses, residents, and students responsible for the care of patients with VTE.

Pharmacogenomics of warfarin: uncovering a piece of the warfarin mystery.

PURPOSE: The literature on the pharmacogenomics of warfarin and the use of genetic testing to optimize initial and maintenance warfarin dosing is reviewed. SUMMARY: Warfarin tablets contain a racemic mixture of R- and S-isomers. The S-isomer is responsible for about 70% of warfarin's anticoagulant effect. Cytochrome P-450 isoenzyme 2C9 (CYP2C9) metabolizes S-warfarin into two inactive metabolites. Genetic variations to the gene encoding CYP2C9 (CYP2C9 ) are known to affect warfarin clearance. Single nucleotide polymorphisms (SNPs) have been identified that clearly influence warfarin metabolism and sensitivity, including SNP variants of CYP2C9 and SNPs in vitamin K epoxide reductase complex subunit 1 (VKORC1), which influence an individual's sensitivity to a given dose. Retrospective studies have evaluated potential factors influencing warfarin metabolism, maintenance dosing, and variability. Several dosing models used to predict warfarin dosing (initial or refinement) have been retrospectively evaluated in diverse patient populations. There are several arguments to support incorporating its use in current clinical practice; however, many expert clinicians in anticoagulation have expressed concern that the push for genotyping patients for CYP2C9 and VKORC1 is premature and not based on good, prospective evidence. Large, randomized controlled trials, in multiple patient populations, comparing clinical dosing to genetic-guided dosing are needed to fully determine the benefits of pharmacogenetic warfarin dosing. CONCLUSION: The increased understanding of pharmacogenomics may improve patient safety during initial dosing of warfarin. At this time, it is unknown if genotype-based dosing will become the standard of care for patients receiving the drug.

Rivaroxaban: an oral direct inhibitor of factor Xa.

PURPOSE: The mechanism of action, pharmacodynamics, pharmacokinetics, efficacy in clinical trials, interactions, adverse effects and toxicity, and place in therapy of rivaroxaban are reviewed. SUMMARY: Rivaroxaban, the first oral, direct factor Xa (FXa) inhibitor to reach Phase III trials, inhibits thrombin generation by both the intrinsic and the tissue factor pathways. It has shown predictable, reversible inhibition of FXa activity, and it may have the ability to inhibit clot-bound FXa. Rivaroxaban is being evaluated for prevention of venous thrombosis in patients undergoing hip or knee arthroplasty, treatment of venous thrombosis, long-term use for secondary prevention of venous thrombosis, and prevention of stroke in atrial fibrillation. To date, only short-term trials have been reported, but rivaroxaban's safety and efficacy appear to be at least equivalent to those of traditional anticoagulants. The results of four studies of primary prevention of venous thrombosis in patients undergoing orthopedic surgery suggest that rivaroxaban 10 mg daily is a promising alternative to low-molecular-weight heparins. Rivaroxaban appears to have a low potential for drug-drug or drug-food interactions. It offers the advantages of a fixed oral dose, rapid onset of action, and predictable and consistent anticoagulation effect, precluding the need for routine monitoring of anticoagulation. CONCLUSION: Rivaroxaban is a promising alternative to traditional anticoagulants for the prevention and treatment of venous thromboembolism and for stroke prevention in atrial fibrillation; it offers once-daily oral administration without the need for routine monitoring.

Implementing anticoagulation management by pharmacists in the inpatient setting.

PURPOSE: This article identifies approaches for implementing an inpatient anticoagulation program involving pharmacists; two successful inpatient anticoagulation programs previously reported in the literature are described with a discussion of steps to consider in developing or expanding such a service. SUMMARY: Two institutions implemented pharmacist-managed anticoagulation services. One institution identified an undesirable incidence of medication-related adverse events occurring in hospitalized patients receiving anticoagulants. Pharmacists were asked to assist. Pharmacist activities included the selection of anticoagulants, patient education, verification of insurance coverage of the patient's anticoagulant, and coordination of follow-up. Physicians were available to assist. At the other institution, the department of pharmacy was asked by the orthopedic surgeons to manage warfarin for the prophylaxis against venous thromboembolism. The pharmacy department worked with the medical staff to gain approval of all policies, guidelines, and protocols to establish an anticoagulation service. Because of the success of the program, the pharmacy department expanded the service beyond warfarin. The steps to establishment of an anticoagulation service are described. The challenges facing such programs are discussed, including the potential anticoagulants in development that will create ongoing challenges in deciding which anticoagulation approach to use and in identifying patients for whom the newer agents may or may not be best suited. CONCLUSION: Requirements for establishing a successful inpatient anticoagulation management program included defining the pharmacist's role in identifying patient needs, gaining support from other health care professionals, designing a program that addresses the needs of the patients, and managing unanticipated issues.