How should unfractionated heparin be monitored in patients transitioning from oral factor Xa inhibitors?
The direct oral anticoagulants (DOACs) include the direct thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban, rivaroxaban, edoxaban, and betrixaban.1 The DOACs have gained widespread use because of their similar or superior efficacy, more predictable pharmacokinetics, and lesser need for monitoring compared with warfarin, the previous gold standard oral anticoagulant.2 However, many situations may warrant transition from a DOAC to a shorter-acting parenteral anticoagulant, such as unfractionated heparin (UFH), for reasons including acute kidney injury, inability to take oral medications, and surgical procedures.3
Commonly used laboratory assays to monitor anticoagulation with UFH include activated partial thromboplastin time (aPTT) and anti-Xa assays.4 Some DOACs, specifically the oral factor Xa inhibitors (OFXais), may cause problems when monitoring UFH via anti-Xa assays because their effects may linger throughout the initial period of UFH treatment. This may result in inaccurate measurement of UFH-specific anticoagulation.5 This situation is becoming frequent because of the increasing preference for use of DOACs over warfarin and of the anti-Xa assay over the aPTT assay.6
Many recommendations are available regarding transitions between DOACs and different anticoagulants, including the transition to UFH.7 Generally, package inserts of OFXais recommend that a transition to a parenteral alternative should dose the parenteral agent at the time the next oral dose is due.8-11 Despite guidance being available for monitoring the transition from DOAC to warfarin, for example, no such guidance is available for monitoring the transition to UFH. This document reviews available literature on monitoring of UFH in patients transitioning from OFXais.
Laboratory considerations related to OFXais
Monitoring of anticoagulation with UFH most commonly utilizes aPTT or anti-Xa assays.4,6,12 The aPTT generally measures the intrinsic and common coagulation pathways, and reports the amount of time in seconds that is required for a clot to form in plasma after activation of the intrinsic pathway.6 The aPTT assay historically has been widely used because it is readily available, easy to perform, and is inexpensive. However, it is susceptible to numerous variables that may affect its accuracy. These include timing and site of blood collection, lot-to-lot variability in reagents, and biologic influences on UFH pharmacokinetics and activity (eg, obesity and lupus anticoagulant). In fact, only approximately half of the variability in aPTT results is explained by the heparin plasma concentration. Because of this variability, each institution is required to establish its own therapeutic aPTT range, which often ranges from 1.5 to 2.5 times the normal value.12
The anti-Xa assay is a more direct measure of plasma heparin concentrations, and is reported in international units (IU) per mL.12 Generally, a plasma heparin concentration range of 0.3 to 0.7 IU/mL by anti-Xa assay is considered to be a therapeutic range.6 Recently, the anti-Xa assay has become more widely used in monitoring UFH because of the shortcomings of the aPTT assay. The anti-Xa assay does not depend on reagents and is less affected by biologic variables than is the aPTT assay. However, in the setting of OFXai use, the anti-Xa assay is not optimal because both OFXai and UFH effects will increase anti-Xa levels, potentially leading to underdosing of UFH until the effect of the OFXai subsides. While OFXais have strong effects on anti-Xa assays, they have little to no effect on aPTT assays.12 Therefore, the role of aPTT monitoring in patients transitioning from OFXais to UFH has been studied.
Literature on monitoring transition from OFXai to UFH
Most current literature evaluating monitoring of patients transitioning from OFXais to UFH involves apixaban and rivaroxaban.3,13,14 The study attempting to most directly answer this question was performed by Smith et al.3 The authors collected retrospective data from patients transitioning from apixaban or rivaroxaban to UFH, with the intent to compare bleeding and thrombotic events between those undergoing aPTT vs anti-Xa monitoring. However, the authors identified very few patients monitored with aPTT (n=7), thus statistical comparison was not performed. Descriptive analysis of the anti-Xa cohort (n=69) identified 1 thrombotic and 10 bleeding events. The majority of infusion rate downtitrations occurred within the first 6 hours, and most uptitrations occurred after 36 hours. The authors concluded this indicates the influence of residual DOAC levels in the early phase of transition to UFH, with effects subsiding over time and resulting in later subtherapeutic anti-Xa levels.
Another retrospective analysis by Macedo et al described the impact of OFXais on anti-Xa monitoring of UFH in patients recently treated with apixaban (n=20) or rivaroxaban (n=30).13 In patients not treated with concomitant UFH, anti-Xa levels above 1 IU/mL occurred in 71% and 55% of patients treated with apixaban and rivaroxaban, respectively. Using data from patients who transitioned from OFXais to UFH (n=28), supratherapeutic anti-Xa levels (above 0.7 IU/mL) were observed in 69% of patients recently treated with apixaban or rivaroxaban vs 21% of historical controls without recent treatment. Therapeutic range was achieved after an average of 3.25 and 1.7 anti-Xa levels with apixaban and rivaroxaban, respectively, at average times of 52 and 39 hours after the last OFXai dose.
A third retrospective study by Ahuja et al assessed the prevalence of OFXai exposure among patients with supratherapeutic anti-Xa levels.14 Among 614 patients with 2 consecutive supratherapeutic anti-Xa levels (above 0.7 IU/mL), 93 (15%) were documented or suspected as being treated with an OFXai (apixaban, n=80; rivaroxaban, n=13) in the previous 72 hours. While no thrombotic events occurred, major bleeding and clinically relevant non-major bleeding each occurred in 3 patients.
Few recommendations are available for monitoring UFH when transitioning from OFXais. The topic is not covered by American College of Chest Physicians guideline on parenteral anticoagulation.4 There is brief mention, however, in a guideline from the International Council for Standardization in Haematology for laboratory measurement of DOACs.15 The guideline notes that special consideration is required for patients treated with DOACs who are bridged with UFH or low-molecular-weight heparin in acute settings. The guideline notes the potential for an additive effect of DOACs on screening tests during the first 24 to 36 hours, and recommends that alternative monitoring strategies for assessing heparin anticoagulation should be used, if required. Thrombin time is listed as an alternative for patients transitioning from OFXAis to UFH.
The remainder of recommendations are offered by authors of the aforementioned studies. For example, Smith et al propose either performing more frequent anti-Xa monitoring should this assay be used, and/or titrating the UFH infusion towards the starting rate once anti-Xa levels begin to decrease.3 The authors also state that in patients with higher thrombotic risk, use of aPTT may be preferred, in which case a baseline level may be considered. When anti-Xa levels are later obtained and enter the target range, typically within 72 hours, anti-Xa monitoring may be reconsidered. Similar recommendations are proposed by Macedo et al and Ahuja et al, with additional mention of the potential for use of an alternative anticoagulant (eg, unmonitored low molecular weight heparin).13,14
An early review of the topic by Faust et al also advises use of aPTT monitoring during the transition from an OFXai to UFH.12 Given the typical half-life of OFXais (8 to 14 hours), the authors propose the transition period should include the first 48 to 72 hours of the UFH infusion. The authors recommend beginning the UFH infusion without a bolus approximately 2 hours before the next scheduled dose of the OFXai. This is followed by aPTT monitoring every 6 to 8 hours for the first 48 hours, or in patients with significant renal or hepatic impairment, up to the first 72 hours. After this period, an anti-Xa assay can be reconsidered, but if two consecutive values are supratherapeutic, consideration should be given to reverting to aPTT monitoring.
Pharmacists should be aware of the additive effect of OFXais on anti-Xa levels and its potential for inaccurate dosing when anti-Xa levels are used to monitor a transition to UFH. Despite a general preference for anti-Xa levels in monitoring UFH, aPTT may be a better measure of UFH anticoagulation in patients transitioning from OFXais to UFH because of its lower susceptibility to the effects of OFXais. Although evidence to guide such transitions is limited both in quantity and quality, consideration should be given to delayed UFH infusions, more intensive anti-Xa monitoring, use of aPTT monitoring as an alternative, and use of alternative anticoagulants.
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- Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-352. doi:10.1016/j.chest.2015.11.026
- Smith AR, Dager WE, Gulseth MP. Transitioning hospitalized patients from rivaroxaban or apixaban to a continuous unfractionated heparin infusion: a retrospective review. Am J Health Syst Pharm. 2020;77(Suppl 3):S59-s65. doi:10.1093/ajhp/zxaa143
- Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e24S-e43S. doi:10.1378/chest.11-2291
- Plum MD, Hedrick JN, Hockman R, Bazydlo L, Palkimas S. The relationship between the initial anti-factor Xa measurement and the duration of direct oral anticoagulant influence in patients transitioning to heparin. Accepted manuscript. Published online July 17, 2020]. Pharmacotherapy. doi:10.1002/phar.2444
- Burnett AE, Sarangarm P. Heparin dosing, monitoring, and reversal. In: J.E. M, Lee MW, eds. Pharmacotherapy Self-Assessment Program, 2020 Book 1. Critical and Urgent Care. American College of Clinical Pharmacy; 2020:93-118.
- Hellerslia V, Mehta P. Transition of Anticoagulants 2019. Thomas Land Publishers Incorporated. Published 2019. Accessed September 17, 2020. https://store.thomasland.com/AnticoagTransitions_2019%20FINAL.pdf
- Eliquis. Package insert. Bristol-Myers Squibb Company; 2019.
- Savaysa. Package insert. Daiichi-Sankyo; 2020.
- Pradaxa. Package insert. Boehringer Ingelheim Pharmaceuticals; 2020.
- Xarelto. Package insert. Janssen Pharmaceuticals Inc; 2020.
- Faust AC, Kanyer D, Wittkowsky AK. Managing transitions from oral factor Xa inhibitors to unfractionated heparin infusions. Am J Health Syst Pharm. 2016;73(24):2037-2041. doi:10.2146/ajhp150596
- Macedo KA, Tatarian P, Eugenio KR. Influence of direct oral anticoagulants on anti-factor Xa measurements utilized for monitoring heparin. Ann Pharmacother. 2018;52(2):154-159. doi:10.1177/1060028017729481
- Ahuja T, Yang I, Huynh Q, Papadopoulos J, Green D. Perils of antithrombotic transitions: effect of oral factor Xa inhibitors on the heparin antifactor Xa assay. Ther Drug Monit. 2020;42(5):737-743. doi:10.1097/ftd.0000000000000774
- Gosselin RC, Adcock DM, Bates SM, et al. International Council for Standardization in Haematology (ICSH) recommendations for laboratory measurement of direct oral anticoagulants. Thromb Haemost. 2018;118(3):437-450. doi:10.1055/s-0038-1627480
Ryan Rodriguez, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
The information presented is current as of September 17, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision making.