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To Measure or Not to Measure: Direct Oral Anticoagulant Laboratory Assay Monitoring in Clinical Practice

To Measure or Not to Measure: Direct Oral Anticoagulant Laboratory Assay Monitoring in Clinical... Hindawi Advances in Hematology Volume 2023, Article ID 9511499, 7 pages https://doi.org/10.1155/2023/9511499 Research Article To Measure or Not to Measure: Direct Oral Anticoagulant Laboratory Assay Monitoring in Clinical Practice 1,2 1 3 2 Tania Ahuja , Veronica Raco , Sharonlin Bhardwaj , and David Green NYU Lanogne Health, Department of Pharmacy, 550 First Avenue, New York, New York, 10016, USA New York University Grossman School of Medicine, Department of Medicine, 550 First Avenue, New York 10016, USA Olive-View UCLA Medical Center, 14445 Olive View Dr, Sylmar, CA 91342, USA Correspondence should be addressed to Tania Ahuja; tania.ahuja@nyumc.org Received 5 July 2022; Revised 28 January 2023; Accepted 7 February 2023; Published 22 February 2023 Academic Editor: Lawrence Rice Copyright © 2023 Tania Ahuja et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Te need for therapeutic drug monitoring of direct oral anticoagulants (DOACs) remains an area of clinical equipoise. Although routine monitoring may be unnecessary given predictable pharmacokinetics in most patients, there may be altered pharma- cokinetics in those with end organ dysfunction, such as those with renal impairment, or with concomitant interacting medi- cations, at extremes of body weight or age, or in those with thromboembolic events in atypical locations. We aimed to assess real- world practices in situations in which DOAC drug-level monitoring was used at a large academic medical center. A retrospective review of the records of patients who had a DOAC drug-specifc activity level checked from 2016 to 2019 was included. A total of 119 patients had 144 DOAC measurements (apixaban (n = 62) and rivaroxaban (n = 57)). Drug-specifc calibrated DOAC levels were within an expected therapeutic range for 110 levels(76%), with 21 levels (15%) above the expected range and 13 levels (9%) below the expected range. Te DOAC levels were checked in the setting of an urgent or emergent procedure in 28 patients (24%), followed by renal failure in 17 patients (14%), a bleeding event in 11 patients (9%), concern for recurrent thromboembolism in 10 patients (8%), thrombophilia in 9 patients (8%), a history of recurrent thromboembolism in 6 patients (5%), extremes of body weight in 7 patients (5%), and unknown reasons in 7 patients (5%). Clinical decision making was infrequently afected by the DOAC monitoring. Terapeutic drug monitoring with DOACs may help predict bleeding events in elderly patients, those with impaired renal function, and in the event of an emergent or urgent procedure. Future studies are needed to target the select patient-specifc scenarios where monitoring DOAC levels may impact clinical outcomes. that may beneft from a DOAC over a VKA were excluded 1. Introduction from the pivotal landmark trials, including those with im- Te direct oral anticoagulants (DOACs) have become paired renal function, extremes of body weight, solid organ preferred over vitamin K antagonists (VKAs), such as transplants, and active cancer [1–9]. Since their approval, warfarin, for stroke prevention in atrial fbrillation (AFib) there has been interest in monitoring drug levels to better and also for the prevention and treatment of venous predict bleeding and thromboembolic risk in select cohorts thromboembolism (VTE) [1–9]. Te DOACs consist of the [10]. National guidelines, such as those of the International factor Xa inhibitors, apixaban, edoxaban, and rivaroxaban Society of Hemostasis and Trombosis (ISTH) and the and the direct thrombin inhibitor, dabigatran. In contrast to National Comprehensive Cancer Network (NCCN), now VKA, the DOACs do not require routine laboratory mon- recommend DOACs for cancer-associated VTE after reg- itoring, and have fewer drug-drug interactions, limited istry data and noninferiority trials found DOACs to be drug-food interactions, and predictable pharmacokinetics in comparable to those who received low molecular weight most patients [1–9]. Notably, although drug-level moni- heparin (LMWH) [11, 12]. However, there remain clinical toring is not routinely required, many cohorts of patients scenarios where a DOAC activity level may assist in clinical 2 Advances in Hematology decision making, such as when suspecting under- or over- characteristics of thromboembolic risk factors or bleeding coagulation, in preparation for a surgical procedure, or in risk factors, and DOAC initiation. Risk factors for throm- the setting of bleeding or the need for thrombolysis. boembolism included documentation of prolonged immo- Since global coagulation laboratory parameters, such as bility, cancer history, known trauma or surgery, or known the activated partial thromboplastin time (aPTT), partial thrombophilia. Other data collected included dosing of thromboplastin time (PT), and international normalized DOAC, indication for DOAC, timing of administration of ratio (INR) are not calibrated to assess the anticoagulant DOAC and timing of DOAC laboratory assay, concomitant efects of DOACs, these are not preferred to assess the safety potential drug interactions, including antiplatelet therapy, or efcacy of the DOACs. Tere remains limited data and history of bleeding or thromboembolic events while on correlating DOAC levels to bleeding, thromboembolic DOAC therapy. In order to characterize whether the DOAC- events, or overall mortality [13, 14]. Given the potential for specifc level was a peak value or trough value, electronic altered pharmacodynamic efects in those with hepatic, medical records were reviewed for documentation of intent renal, or cardiac dysfunction, extremes of body weight or for peak (2–4 hours for apixaban or rivaroxaban and 2 hours for dabigatran) or trough (before next dose) or a random age, and/or thrombophilia, a hematologist may often be consulted on cases where the use of a calibrated drug assay sample, as documented in notes by the ordering physician may assist in the selection of the dose of anticoagulation. along with timing of laboratory result. If a corresponding Still, there remains limited evidence to support this, and the note did not specify the intent, DOAC-specifc levels were optimal therapeutic ranges vary based on assay, type of characterized by the date/time of the sample compared to DOAC, and dose of DOAC [15–18]. Further, the need for the documentation of the administration time of the DOAC. a DOAC-calibrated drug assay may assist with a clinical In the absence of documentation or known timing of ad- decision regarding anticoagulation reversal in the event of ministration of DOAC, samples were characterized as bleeding, the need for thrombolysis for an ischemic stroke, random sampling. Measured DOAC levels were compared or for other emergent procedures [12, 19–22]. At New York to expected steady-state ranges of DOAC levels based on University Langone Health, a large academic medical center, previously published data. Data were managed utilizing Research Electronic Data Capture (REDCap), a secure in- antithrombotic stewardship focusing on selection of anti- coagulation, dosing, and monitoring is embedded into formatics system designed to support data collection across clinical decision-making tools available in the electronic various research disciplines [23]. medical record. Subject matter content is reviewed through Te primary outcome was the percentage of DOAC assay the Antithrombotic and Hemostatic Terapy Oversight levels checked based on clinical indication. Secondary Group (ATHOG), consisting of interdisciplinary in- outcomes include the percentage of levels within an expected volvement from physicians in hematology, cardiology, therapeutic range and whether testing afected clinical neurology, vascular surgery, and interventional radiology, change in antithrombotic management. In addition, the along with clinical pharmacotherapy specialists, nursing, safety and efcacy of antithrombotic therapy were evaluated. and hematology laboratory representatives. In September of Safety was assessed by the presence of any bleeding events 2016, DOAC laboratory assays calibrated to drug levels were while on antithrombotic therapy. Major bleeding events made available. Given the limited data published to support were defned using the International Society of Trombosis dose adjustments, ATHOG provided guidance that was and Hemostasis criteria: fatal bleeding, and/or symptomatic communicated to committee members but did not formally bleeding in a critical area or organ (including intracranial, implement a guideline for which clinical scenarios to check intraspinal, intraocular, retroperitoneal, intraarticular, levels in, or how to correlate them with bleeding or pericardial, or intramuscular bleeding with compartment thromboembolic events. Te aim of our retrospective review syndrome), and/or a greater than 2 g/dl decrease in he- was to determine the indications for where clinicians moglobin or bleeding necessitating 2 or 3 units of whole checked these levels and how the levels assisted in the overall blood or packed red blood cells [24]. Clinically relevant management of patients on a DOAC. minor bleeding was defned as overt bleeding noted by a physician that was not attributed to an alternative source. Efcacy was assessed by the lack of any thromboembolic 2. Methods events, including stroke or any VTE, while on therapy with Tis was a single-centered, institutional review board (IRB)- a DOAC. In addition, if changes in DOAC therapy occurred, or antithrombotic therapy was discontinued, the rationale approved, retrospective cohort study at NYULH of adult patients prescribed a DOAC with a corresponding DOAC for discontinuations were assessed. Reasons for the dis- continuation was included bleeding events, thrombocyto- drug-specifc level from September 2016 to January 2019. Tese patients were included if they were at least 18 years of penia, acute kidney injury (AKI), defned by the RIFLE age and received anticoagulation with a DOAC, including criteria, or not classifed [25]. dabigatran, apixaban, or rivaroxaban. Since edoxaban was Venous blood samples were drawn to assess DOAC not available on hospital formularies, we did not have concentrations. Dabigatran levels were available for testing DOAC drug-level assessments available for this drug. using the HemosIL DTI assay. Apixaban and rivaroxaban Data collection consisted of a retrospective review of levels were measured using the chromogenic HemosIL liquid anti-Xa assay (Instrumentation Laboratory, baseline demographics, medical history, surgical history, or trauma within 6 months of anticoagulation initiation, United States). All assays were measured on an ACL TOP Advances in Hematology 3 mL (5–173 ng/mL) for the 2.5 mg and 5 mg doses, re- 500 coagulometer (Instrumentation Laboratory, United States). spectively. Te remaining 61 levels were classifed as random sampling in the setting of bleeding event or need for urgent Patient characteristics were described as proportions for categorical variables and as medians and interquartile ranges procedure or unknown reasons. for continuous variables without a normal distribution. Te Clinical decisions regarding DOAC management, in- coefcient of variation was calculated for all DOAC levels cluding dose adjustments, changes in antithrombotic ther- based on expected therapeutic ranges and renal function. Data apy, and/or discontinuations as a result of DOAC were analyzed using the Software Package for Statistics and monitoring, occurred in 39 (33%) of the measurements Simulation (IBM SPSS version 22, IMB Corp. Armonk, NY). performed. Tis resulted in a decrease in DOAC dose (n � 20), an increase in DOAC dose (n � 5), the enabling of a procedure (n � 22), and the cancellation of a procedure 3. Results (n � 1). A breakdowxn of changes in DOAC dose can be 3.1. Patient Characteristics. In total, 119 patients underwent found in Figure 1. 144 DOAC measurements [apixaban (n = 62) and rivarox- aban (n = 57), with no dabigatran levels checked] during the study period. Table 1 presents the demographics and clinical 3.4. Secondary Outcomes: Recurrent Tromboembolic Events characteristics of the patients that had DOAC levels mea- and Bleeding. Tere were 15 patients who had thrombo- embolic events during DOAC therapy. Out of these, 9 were sured (50% female), median age 74 (27–102) years, with 14% of the cohort having a body mass index (BMI) greater than recurrent VTEs and 6 were ischemic strokes. In addition, 3 of these 15 patients had a correspondingly below-level 35 and 28% of the cohort having renal impairment at the time of DOAC testing. Baseline characteristics did not difer DOAC level at the time of the event, including 1 patient with antiphospholipid syndrome. Tere were 19 patients according to DOAC. Te majority of DOAC levels occurred during acute hospitalization (68, 58%), with the remainder (16%) that experienced a bleeding event during treatment with a DOAC, with 4 bleeds at a critical site, including 3 in outpatient clinics. Te clinical referring service for DOAC monitoring in the outpatient setting was predominantly intracranial bleeds. For the intracranial bleeds, 2 random DOAC levels assessed around the time of the bleed were hematology (40, 78%). Indications for anticoagulation therapy were the treatment of VTE in 59 (50%) followed by above the desired therapeutic range. Te remaining 15 stroke prevention with AF in 46 (39%). bleeding events were classifed as clinically overt, with 6 patients on concomitant antiplatelet therapy. Out of the 19 bleeds, 13 patients had impaired renal function, defned as 3.2. Primary Outcome: Indications for DOAC Level a creatinine clearance (CrCL) less than 60 mL/min at the Monitoring. Te DOAC levels were checked in the setting of time of the bleeding event. For patients that had a DOAC an urgent or emergent procedure in 38 patients (32%), level checked in the setting of an emergent or urgent pro- followed by renal failure in 17 patients (14%), a bleeding cedure (n � 14), 4 patients experienced bleed events, of event in 11 patients (9%), concern for recurrent thrombo- which 3 occurred on apixaban and 1 on rivaroxaban. All embolism in 10 patients (8%), thrombophilia in 9 patients procedures occurred emergently, within 12–24 hours after (8%), a history of recurrent thromboembolism in 6 patients the DOAC was held, with levels below the desired thera- (5%), and extremes of body weight in 21 patients (18%). peutic range. Tere was once a procedure that was cancelled. Tere were 7 patients (20%) who did not have a clear in- Further breakdown of ranges of levels and percentage of dication for DOAC level measurement documented. Te levels within and out of range can be found in the sup- breakdown of DOAC levels checked by apixaban or rivar- plementary fles in Supplementary Tables 1 and 2 and DOAC oxaban can be found in Table 2. levels plotted according to time, dose and renal function can be found in Supplementary Figures 1–4. 3.3. Secondary Outcomes: DOAC Drug Levels and Clinical Management. DOAC drug levels were within the expected 4. Discussion range for 110 levels(76%), with 21 levels (14.5%) above the expected range and 13 levels (9%) below the expected range. Tis retrospective study evaluated the clinical utility of Te type of DOAC used, gender, and setting of testing did DOAC level monitoring at a large academic medical center. not difer according to the drug-level result. Tere were We found DOAC levels had implications for clinical a total of 16 peaks and 23 troughs checked for rivaroxaban decision-making in the setting of impaired renal function, 20 mg daily, with a median value of 315.1 ng/mL (19–517 ng/ elderly patients, and those needing emergent or urgent mL) and 98 ng/mL (14–209 ng/mL), respectively. Tere were procedures. However, routine DOAC level monitoring may a total of 25 peaks and 19 troughs checked for apixaban, with be unnecessary, as clinical decision-making was infrequently 11 peaks and 11 troughs with the 2.5 mg twice daily regimen afected by these results in our cohort. Our data highlight and 14 peaks and 8 troughs for the 5 mg twice daily regimen. that most DOAC levels were within an expected therapeutic Te median apixaban peak values were 259 ng/mL range, consistent with efects desired in those with VTE, AF, (102–657 ng/mL) and 255 ng/mL (46–477 ng/mL) for the or cancer-associated thrombosis (CAT) [3–9, 11]. Still, in 2.5 mg and 5 mg doses, respectively. Te median apixaban unique circumstances, knowledge of the DOAC drug level trough values were 105 ng/mL (41–274 ng/mL) and 91 ng/ may help better predict bleeding or thrombosis [26–30]. 4 Advances in Hematology Table 1: Patient baseline characteristics. Overall N � 119 Apixaban n � 62 Rivaroxaban n � 57 Age, years: median (IQR) 74 (27–102) 78 (33–102) 69 (27–91) <65 years 37 (31) 13 (21) 24 (42) 65–74 years 26 (22) 11 (18) 15 (26) ≥75 years 56 (47) 38 (61) 18 (32) Sex Male 60 (50) 31 (50) 29 (51) Female 59 (50) 31 (50) 28 (49) Body Mass index, kg/m : median (IQR) 26.8 (17–64) 26.0 (17–49) 26.9 (17–64) ≥35 16 (13) 6 (10) 10 (18) 30–34.9 18 (15) 11 (18) 7 (12) 25–29.9 43 (36) 22 (35) 21 (37) 18.5–24.9 33 (28) 17 (27) 16 (28) <18.5 4 (3) 3 (5) 1 (2) Unknown 5 (4) 3 (5) 2 (3) Past medical history Gastrointestinal bleed 8 (7) 7 (11) 1 (2) Stroke/TIA 28 (24) 18 (29) 10 (18) eGFR <60 mL/min 33 (28) 26 (42) 7 (12) Diabetes 27 (23) 18 (29) 9 (16) Indication for anticoagulant Stroke prevention with atrial fbrillation 49 (41) 14 (12) 35 (29) Acute PE 28 (24) 16 (28) 12 (19) Chronic PE 14 (12) 12 (21) 2 (3) Acute DVT 31 (26) 18 (32) 13 (21) Chronic DVT 24 (20) 19 (33) 5 (8) Other 9 (8) 4 (7) 5 (8) Table 2: Indication for laboratory assessment of DOAC level. Overall N � 119 Apixaban n � 62 Rivaroxaban n � 57 Urgent/emergent procedure 38 (32) 28 (45) 10 (18) Acute kidney injury 17 (14) 10 (16) 7 (12) Bleed event on DOAC 11 (9) 5 (8) 6 (11) Recurrent VTE on DOAC 10 (8) 5 (8) 5 (9) Trombophilia 9 (8) 0 (0) 9 (16) Other 7 (6) 2 (3) 5 (9) History of recurrent VTE pre-DOAC 6 (5) 0 (0) 6 (11) High body weight 16 (13) 10 (16) 6 (11) Low body weight 5 (4) 2 (3) 3 (5) Although there are no ofcial recommendations to advise events due to vascular calcifcation and also bleeding events when DOAC drug levels may be best utilized, our data and as hepatic and renal function decline with age, making evidence to date suggest that bleed risk may be better antithrombotic therapy a double-edged sword [26, 28]. predicted in these circumstances [26–30]. Future studies evaluating DOAC drug levels in elderly pa- We observed bleeding events most commonly in the in- tients specifcally may help guide clinical decision-making in patient setting in those with renal impairment, suggesting the this cohort. Lastly, we found DOAC drug levels checked in the relationship of elevated DOAC drug concentrations in this setting. Tis may be a case of correlation rather than causation, setting of urgent or emergent procedures. We observed and the knowledge of such levels may have little impact on bleeding most commonly when the procedure was not clinical care, with the exception of consideration for hemostatic delayed more than 24 hours from the last known dose of the agents, such as the use of prothrombin complex concentrates DOAC, suggesting that the DOAC drug-level knowledge did or other agents for reversal, such as andexanet alfa. not result in a delay in the emergent procedure. Still, Older age has been demonstrated to be a risk factor for knowledge at this level may help clinicians anticipate having a DOAC level above the expected range [26, 28, 31]. bleeding and have hemostatic agents available as necessary. Notably, the median age for our cohort was 74 years, much Even though cutofs for peak and trough values for apixaban older than the patients enrolled in the landmark trials [6–9]. and rivaroxaban have been provided from the landmark Elderly patients are at increased risk of thromboembolic trials, it is unknown if these trough values are considered Advances in Hematology 5 Data Availability Te data used to support the fndings of this study are available from the corresponding author upon request. Additional Points 4 Te need for routine DOAC-calibrated drugs levels is likely unnecessary. In real-world prescribing of DOACs, we ob- 3 served drug levels monitored in certain clinical scenarios, specifcally in elderly patients, those with renal impairment, or those needing urgent or emergent procedures. Future Rivaroxaban Apixaban studies are necessary to establish associations between drug Decreased levels and clinical outcomes. Increased Figure 1: Change in DOAC dose. Disclosure Preliminary fndings from this manuscript were presented in safe to prevent procedural-related bleeding [21, 32–34]. poster format at the 27th International Society of Trom- Tough preprocedure DOAC troughs of less than 30 ng/mL bosis and Hemostasis (ISTH) Meeting under the title “Direct have been considered safe to proceed without an impact on Oral Anticoagulant Laboratory Assay Assessment at a Large bleed risk, timing from the last dose may better predict Academic Medical Center” (PB1678). actual bleed risk [21, 34]. In the PAUSE trial, DOACs were interrupted for 24 hours for low bleed-risk procedures and Conflicts of Interest 48 hours for high bleed-risk procedures [33]. However, with emergent procedures, 24–48 hours may be too long, and Te authors declare that there are no conficts of interest. preprocedure DOAC levels may better help predict post- procedure bleed risk [29]. Acknowledgments 5. Conclusion Te authors would like to thank and acknowledge Tatcher Heumann, MD, for his contribution to background search DOAC-calibrated assays to measure plasma concentrations and Maria Spilios, PharmD, for her contribution to data are often limited by availability, lack of rapid turnaround, collection. and lack of guidelines for clinical management of dose based on level. In addition, data correlating drug levels to Supplementary Materials clinical outcomes, such as recurrent thromboembolism or bleeding events remains limited. We observed the greatest Table 1: Mean, median, and range of levels. Table 2: Per- use of these drug levels in certain clinical scenarios for centage of levels in and out of range. Figure 1: Rivaroxaban acutely hospitalized patients at high risk for bleeding due to levels with a 20 mg daily dose. Figure 2: Apixaban levels in all old age or renal dysfunction. Future studies are necessary in doses. Figure 3: Apixaban DOAC levels plotted against renal these specifc clinical scenarios or when there may be function. Figure 4: Rivaroxaban DOAC levels plotted against concern for unpredictable pharmacokinetics to better renal function. (Supplementary Materials) predict the safety and tolerability of a DOAC. In addition, for those patients presenting to the hospital with bleeding, References a DOAC-specifc level may help predict the need for he- mostatic or reversal agents. As DOACs have overtaken [1] S. Schulman, C. Kearon, A. K. 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To Measure or Not to Measure: Direct Oral Anticoagulant Laboratory Assay Monitoring in Clinical Practice

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Hindawi Advances in Hematology Volume 2023, Article ID 9511499, 7 pages https://doi.org/10.1155/2023/9511499 Research Article To Measure or Not to Measure: Direct Oral Anticoagulant Laboratory Assay Monitoring in Clinical Practice 1,2 1 3 2 Tania Ahuja , Veronica Raco , Sharonlin Bhardwaj , and David Green NYU Lanogne Health, Department of Pharmacy, 550 First Avenue, New York, New York, 10016, USA New York University Grossman School of Medicine, Department of Medicine, 550 First Avenue, New York 10016, USA Olive-View UCLA Medical Center, 14445 Olive View Dr, Sylmar, CA 91342, USA Correspondence should be addressed to Tania Ahuja; tania.ahuja@nyumc.org Received 5 July 2022; Revised 28 January 2023; Accepted 7 February 2023; Published 22 February 2023 Academic Editor: Lawrence Rice Copyright © 2023 Tania Ahuja et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Te need for therapeutic drug monitoring of direct oral anticoagulants (DOACs) remains an area of clinical equipoise. Although routine monitoring may be unnecessary given predictable pharmacokinetics in most patients, there may be altered pharma- cokinetics in those with end organ dysfunction, such as those with renal impairment, or with concomitant interacting medi- cations, at extremes of body weight or age, or in those with thromboembolic events in atypical locations. We aimed to assess real- world practices in situations in which DOAC drug-level monitoring was used at a large academic medical center. A retrospective review of the records of patients who had a DOAC drug-specifc activity level checked from 2016 to 2019 was included. A total of 119 patients had 144 DOAC measurements (apixaban (n = 62) and rivaroxaban (n = 57)). Drug-specifc calibrated DOAC levels were within an expected therapeutic range for 110 levels(76%), with 21 levels (15%) above the expected range and 13 levels (9%) below the expected range. Te DOAC levels were checked in the setting of an urgent or emergent procedure in 28 patients (24%), followed by renal failure in 17 patients (14%), a bleeding event in 11 patients (9%), concern for recurrent thromboembolism in 10 patients (8%), thrombophilia in 9 patients (8%), a history of recurrent thromboembolism in 6 patients (5%), extremes of body weight in 7 patients (5%), and unknown reasons in 7 patients (5%). Clinical decision making was infrequently afected by the DOAC monitoring. Terapeutic drug monitoring with DOACs may help predict bleeding events in elderly patients, those with impaired renal function, and in the event of an emergent or urgent procedure. Future studies are needed to target the select patient-specifc scenarios where monitoring DOAC levels may impact clinical outcomes. that may beneft from a DOAC over a VKA were excluded 1. Introduction from the pivotal landmark trials, including those with im- Te direct oral anticoagulants (DOACs) have become paired renal function, extremes of body weight, solid organ preferred over vitamin K antagonists (VKAs), such as transplants, and active cancer [1–9]. Since their approval, warfarin, for stroke prevention in atrial fbrillation (AFib) there has been interest in monitoring drug levels to better and also for the prevention and treatment of venous predict bleeding and thromboembolic risk in select cohorts thromboembolism (VTE) [1–9]. Te DOACs consist of the [10]. National guidelines, such as those of the International factor Xa inhibitors, apixaban, edoxaban, and rivaroxaban Society of Hemostasis and Trombosis (ISTH) and the and the direct thrombin inhibitor, dabigatran. In contrast to National Comprehensive Cancer Network (NCCN), now VKA, the DOACs do not require routine laboratory mon- recommend DOACs for cancer-associated VTE after reg- itoring, and have fewer drug-drug interactions, limited istry data and noninferiority trials found DOACs to be drug-food interactions, and predictable pharmacokinetics in comparable to those who received low molecular weight most patients [1–9]. Notably, although drug-level moni- heparin (LMWH) [11, 12]. However, there remain clinical toring is not routinely required, many cohorts of patients scenarios where a DOAC activity level may assist in clinical 2 Advances in Hematology decision making, such as when suspecting under- or over- characteristics of thromboembolic risk factors or bleeding coagulation, in preparation for a surgical procedure, or in risk factors, and DOAC initiation. Risk factors for throm- the setting of bleeding or the need for thrombolysis. boembolism included documentation of prolonged immo- Since global coagulation laboratory parameters, such as bility, cancer history, known trauma or surgery, or known the activated partial thromboplastin time (aPTT), partial thrombophilia. Other data collected included dosing of thromboplastin time (PT), and international normalized DOAC, indication for DOAC, timing of administration of ratio (INR) are not calibrated to assess the anticoagulant DOAC and timing of DOAC laboratory assay, concomitant efects of DOACs, these are not preferred to assess the safety potential drug interactions, including antiplatelet therapy, or efcacy of the DOACs. Tere remains limited data and history of bleeding or thromboembolic events while on correlating DOAC levels to bleeding, thromboembolic DOAC therapy. In order to characterize whether the DOAC- events, or overall mortality [13, 14]. Given the potential for specifc level was a peak value or trough value, electronic altered pharmacodynamic efects in those with hepatic, medical records were reviewed for documentation of intent renal, or cardiac dysfunction, extremes of body weight or for peak (2–4 hours for apixaban or rivaroxaban and 2 hours for dabigatran) or trough (before next dose) or a random age, and/or thrombophilia, a hematologist may often be consulted on cases where the use of a calibrated drug assay sample, as documented in notes by the ordering physician may assist in the selection of the dose of anticoagulation. along with timing of laboratory result. If a corresponding Still, there remains limited evidence to support this, and the note did not specify the intent, DOAC-specifc levels were optimal therapeutic ranges vary based on assay, type of characterized by the date/time of the sample compared to DOAC, and dose of DOAC [15–18]. Further, the need for the documentation of the administration time of the DOAC. a DOAC-calibrated drug assay may assist with a clinical In the absence of documentation or known timing of ad- decision regarding anticoagulation reversal in the event of ministration of DOAC, samples were characterized as bleeding, the need for thrombolysis for an ischemic stroke, random sampling. Measured DOAC levels were compared or for other emergent procedures [12, 19–22]. At New York to expected steady-state ranges of DOAC levels based on University Langone Health, a large academic medical center, previously published data. Data were managed utilizing Research Electronic Data Capture (REDCap), a secure in- antithrombotic stewardship focusing on selection of anti- coagulation, dosing, and monitoring is embedded into formatics system designed to support data collection across clinical decision-making tools available in the electronic various research disciplines [23]. medical record. Subject matter content is reviewed through Te primary outcome was the percentage of DOAC assay the Antithrombotic and Hemostatic Terapy Oversight levels checked based on clinical indication. Secondary Group (ATHOG), consisting of interdisciplinary in- outcomes include the percentage of levels within an expected volvement from physicians in hematology, cardiology, therapeutic range and whether testing afected clinical neurology, vascular surgery, and interventional radiology, change in antithrombotic management. In addition, the along with clinical pharmacotherapy specialists, nursing, safety and efcacy of antithrombotic therapy were evaluated. and hematology laboratory representatives. In September of Safety was assessed by the presence of any bleeding events 2016, DOAC laboratory assays calibrated to drug levels were while on antithrombotic therapy. Major bleeding events made available. Given the limited data published to support were defned using the International Society of Trombosis dose adjustments, ATHOG provided guidance that was and Hemostasis criteria: fatal bleeding, and/or symptomatic communicated to committee members but did not formally bleeding in a critical area or organ (including intracranial, implement a guideline for which clinical scenarios to check intraspinal, intraocular, retroperitoneal, intraarticular, levels in, or how to correlate them with bleeding or pericardial, or intramuscular bleeding with compartment thromboembolic events. Te aim of our retrospective review syndrome), and/or a greater than 2 g/dl decrease in he- was to determine the indications for where clinicians moglobin or bleeding necessitating 2 or 3 units of whole checked these levels and how the levels assisted in the overall blood or packed red blood cells [24]. Clinically relevant management of patients on a DOAC. minor bleeding was defned as overt bleeding noted by a physician that was not attributed to an alternative source. Efcacy was assessed by the lack of any thromboembolic 2. Methods events, including stroke or any VTE, while on therapy with Tis was a single-centered, institutional review board (IRB)- a DOAC. In addition, if changes in DOAC therapy occurred, or antithrombotic therapy was discontinued, the rationale approved, retrospective cohort study at NYULH of adult patients prescribed a DOAC with a corresponding DOAC for discontinuations were assessed. Reasons for the dis- continuation was included bleeding events, thrombocyto- drug-specifc level from September 2016 to January 2019. Tese patients were included if they were at least 18 years of penia, acute kidney injury (AKI), defned by the RIFLE age and received anticoagulation with a DOAC, including criteria, or not classifed [25]. dabigatran, apixaban, or rivaroxaban. Since edoxaban was Venous blood samples were drawn to assess DOAC not available on hospital formularies, we did not have concentrations. Dabigatran levels were available for testing DOAC drug-level assessments available for this drug. using the HemosIL DTI assay. Apixaban and rivaroxaban Data collection consisted of a retrospective review of levels were measured using the chromogenic HemosIL liquid anti-Xa assay (Instrumentation Laboratory, baseline demographics, medical history, surgical history, or trauma within 6 months of anticoagulation initiation, United States). All assays were measured on an ACL TOP Advances in Hematology 3 mL (5–173 ng/mL) for the 2.5 mg and 5 mg doses, re- 500 coagulometer (Instrumentation Laboratory, United States). spectively. Te remaining 61 levels were classifed as random sampling in the setting of bleeding event or need for urgent Patient characteristics were described as proportions for categorical variables and as medians and interquartile ranges procedure or unknown reasons. for continuous variables without a normal distribution. Te Clinical decisions regarding DOAC management, in- coefcient of variation was calculated for all DOAC levels cluding dose adjustments, changes in antithrombotic ther- based on expected therapeutic ranges and renal function. Data apy, and/or discontinuations as a result of DOAC were analyzed using the Software Package for Statistics and monitoring, occurred in 39 (33%) of the measurements Simulation (IBM SPSS version 22, IMB Corp. Armonk, NY). performed. Tis resulted in a decrease in DOAC dose (n � 20), an increase in DOAC dose (n � 5), the enabling of a procedure (n � 22), and the cancellation of a procedure 3. Results (n � 1). A breakdowxn of changes in DOAC dose can be 3.1. Patient Characteristics. In total, 119 patients underwent found in Figure 1. 144 DOAC measurements [apixaban (n = 62) and rivarox- aban (n = 57), with no dabigatran levels checked] during the study period. Table 1 presents the demographics and clinical 3.4. Secondary Outcomes: Recurrent Tromboembolic Events characteristics of the patients that had DOAC levels mea- and Bleeding. Tere were 15 patients who had thrombo- embolic events during DOAC therapy. Out of these, 9 were sured (50% female), median age 74 (27–102) years, with 14% of the cohort having a body mass index (BMI) greater than recurrent VTEs and 6 were ischemic strokes. In addition, 3 of these 15 patients had a correspondingly below-level 35 and 28% of the cohort having renal impairment at the time of DOAC testing. Baseline characteristics did not difer DOAC level at the time of the event, including 1 patient with antiphospholipid syndrome. Tere were 19 patients according to DOAC. Te majority of DOAC levels occurred during acute hospitalization (68, 58%), with the remainder (16%) that experienced a bleeding event during treatment with a DOAC, with 4 bleeds at a critical site, including 3 in outpatient clinics. Te clinical referring service for DOAC monitoring in the outpatient setting was predominantly intracranial bleeds. For the intracranial bleeds, 2 random DOAC levels assessed around the time of the bleed were hematology (40, 78%). Indications for anticoagulation therapy were the treatment of VTE in 59 (50%) followed by above the desired therapeutic range. Te remaining 15 stroke prevention with AF in 46 (39%). bleeding events were classifed as clinically overt, with 6 patients on concomitant antiplatelet therapy. Out of the 19 bleeds, 13 patients had impaired renal function, defned as 3.2. Primary Outcome: Indications for DOAC Level a creatinine clearance (CrCL) less than 60 mL/min at the Monitoring. Te DOAC levels were checked in the setting of time of the bleeding event. For patients that had a DOAC an urgent or emergent procedure in 38 patients (32%), level checked in the setting of an emergent or urgent pro- followed by renal failure in 17 patients (14%), a bleeding cedure (n � 14), 4 patients experienced bleed events, of event in 11 patients (9%), concern for recurrent thrombo- which 3 occurred on apixaban and 1 on rivaroxaban. All embolism in 10 patients (8%), thrombophilia in 9 patients procedures occurred emergently, within 12–24 hours after (8%), a history of recurrent thromboembolism in 6 patients the DOAC was held, with levels below the desired thera- (5%), and extremes of body weight in 21 patients (18%). peutic range. Tere was once a procedure that was cancelled. Tere were 7 patients (20%) who did not have a clear in- Further breakdown of ranges of levels and percentage of dication for DOAC level measurement documented. Te levels within and out of range can be found in the sup- breakdown of DOAC levels checked by apixaban or rivar- plementary fles in Supplementary Tables 1 and 2 and DOAC oxaban can be found in Table 2. levels plotted according to time, dose and renal function can be found in Supplementary Figures 1–4. 3.3. Secondary Outcomes: DOAC Drug Levels and Clinical Management. DOAC drug levels were within the expected 4. Discussion range for 110 levels(76%), with 21 levels (14.5%) above the expected range and 13 levels (9%) below the expected range. Tis retrospective study evaluated the clinical utility of Te type of DOAC used, gender, and setting of testing did DOAC level monitoring at a large academic medical center. not difer according to the drug-level result. Tere were We found DOAC levels had implications for clinical a total of 16 peaks and 23 troughs checked for rivaroxaban decision-making in the setting of impaired renal function, 20 mg daily, with a median value of 315.1 ng/mL (19–517 ng/ elderly patients, and those needing emergent or urgent mL) and 98 ng/mL (14–209 ng/mL), respectively. Tere were procedures. However, routine DOAC level monitoring may a total of 25 peaks and 19 troughs checked for apixaban, with be unnecessary, as clinical decision-making was infrequently 11 peaks and 11 troughs with the 2.5 mg twice daily regimen afected by these results in our cohort. Our data highlight and 14 peaks and 8 troughs for the 5 mg twice daily regimen. that most DOAC levels were within an expected therapeutic Te median apixaban peak values were 259 ng/mL range, consistent with efects desired in those with VTE, AF, (102–657 ng/mL) and 255 ng/mL (46–477 ng/mL) for the or cancer-associated thrombosis (CAT) [3–9, 11]. Still, in 2.5 mg and 5 mg doses, respectively. Te median apixaban unique circumstances, knowledge of the DOAC drug level trough values were 105 ng/mL (41–274 ng/mL) and 91 ng/ may help better predict bleeding or thrombosis [26–30]. 4 Advances in Hematology Table 1: Patient baseline characteristics. Overall N � 119 Apixaban n � 62 Rivaroxaban n � 57 Age, years: median (IQR) 74 (27–102) 78 (33–102) 69 (27–91) <65 years 37 (31) 13 (21) 24 (42) 65–74 years 26 (22) 11 (18) 15 (26) ≥75 years 56 (47) 38 (61) 18 (32) Sex Male 60 (50) 31 (50) 29 (51) Female 59 (50) 31 (50) 28 (49) Body Mass index, kg/m : median (IQR) 26.8 (17–64) 26.0 (17–49) 26.9 (17–64) ≥35 16 (13) 6 (10) 10 (18) 30–34.9 18 (15) 11 (18) 7 (12) 25–29.9 43 (36) 22 (35) 21 (37) 18.5–24.9 33 (28) 17 (27) 16 (28) <18.5 4 (3) 3 (5) 1 (2) Unknown 5 (4) 3 (5) 2 (3) Past medical history Gastrointestinal bleed 8 (7) 7 (11) 1 (2) Stroke/TIA 28 (24) 18 (29) 10 (18) eGFR <60 mL/min 33 (28) 26 (42) 7 (12) Diabetes 27 (23) 18 (29) 9 (16) Indication for anticoagulant Stroke prevention with atrial fbrillation 49 (41) 14 (12) 35 (29) Acute PE 28 (24) 16 (28) 12 (19) Chronic PE 14 (12) 12 (21) 2 (3) Acute DVT 31 (26) 18 (32) 13 (21) Chronic DVT 24 (20) 19 (33) 5 (8) Other 9 (8) 4 (7) 5 (8) Table 2: Indication for laboratory assessment of DOAC level. Overall N � 119 Apixaban n � 62 Rivaroxaban n � 57 Urgent/emergent procedure 38 (32) 28 (45) 10 (18) Acute kidney injury 17 (14) 10 (16) 7 (12) Bleed event on DOAC 11 (9) 5 (8) 6 (11) Recurrent VTE on DOAC 10 (8) 5 (8) 5 (9) Trombophilia 9 (8) 0 (0) 9 (16) Other 7 (6) 2 (3) 5 (9) History of recurrent VTE pre-DOAC 6 (5) 0 (0) 6 (11) High body weight 16 (13) 10 (16) 6 (11) Low body weight 5 (4) 2 (3) 3 (5) Although there are no ofcial recommendations to advise events due to vascular calcifcation and also bleeding events when DOAC drug levels may be best utilized, our data and as hepatic and renal function decline with age, making evidence to date suggest that bleed risk may be better antithrombotic therapy a double-edged sword [26, 28]. predicted in these circumstances [26–30]. Future studies evaluating DOAC drug levels in elderly pa- We observed bleeding events most commonly in the in- tients specifcally may help guide clinical decision-making in patient setting in those with renal impairment, suggesting the this cohort. Lastly, we found DOAC drug levels checked in the relationship of elevated DOAC drug concentrations in this setting. Tis may be a case of correlation rather than causation, setting of urgent or emergent procedures. We observed and the knowledge of such levels may have little impact on bleeding most commonly when the procedure was not clinical care, with the exception of consideration for hemostatic delayed more than 24 hours from the last known dose of the agents, such as the use of prothrombin complex concentrates DOAC, suggesting that the DOAC drug-level knowledge did or other agents for reversal, such as andexanet alfa. not result in a delay in the emergent procedure. Still, Older age has been demonstrated to be a risk factor for knowledge at this level may help clinicians anticipate having a DOAC level above the expected range [26, 28, 31]. bleeding and have hemostatic agents available as necessary. Notably, the median age for our cohort was 74 years, much Even though cutofs for peak and trough values for apixaban older than the patients enrolled in the landmark trials [6–9]. and rivaroxaban have been provided from the landmark Elderly patients are at increased risk of thromboembolic trials, it is unknown if these trough values are considered Advances in Hematology 5 Data Availability Te data used to support the fndings of this study are available from the corresponding author upon request. Additional Points 4 Te need for routine DOAC-calibrated drugs levels is likely unnecessary. In real-world prescribing of DOACs, we ob- 3 served drug levels monitored in certain clinical scenarios, specifcally in elderly patients, those with renal impairment, or those needing urgent or emergent procedures. Future Rivaroxaban Apixaban studies are necessary to establish associations between drug Decreased levels and clinical outcomes. Increased Figure 1: Change in DOAC dose. Disclosure Preliminary fndings from this manuscript were presented in safe to prevent procedural-related bleeding [21, 32–34]. poster format at the 27th International Society of Trom- Tough preprocedure DOAC troughs of less than 30 ng/mL bosis and Hemostasis (ISTH) Meeting under the title “Direct have been considered safe to proceed without an impact on Oral Anticoagulant Laboratory Assay Assessment at a Large bleed risk, timing from the last dose may better predict Academic Medical Center” (PB1678). actual bleed risk [21, 34]. In the PAUSE trial, DOACs were interrupted for 24 hours for low bleed-risk procedures and Conflicts of Interest 48 hours for high bleed-risk procedures [33]. However, with emergent procedures, 24–48 hours may be too long, and Te authors declare that there are no conficts of interest. preprocedure DOAC levels may better help predict post- procedure bleed risk [29]. Acknowledgments 5. Conclusion Te authors would like to thank and acknowledge Tatcher Heumann, MD, for his contribution to background search DOAC-calibrated assays to measure plasma concentrations and Maria Spilios, PharmD, for her contribution to data are often limited by availability, lack of rapid turnaround, collection. and lack of guidelines for clinical management of dose based on level. In addition, data correlating drug levels to Supplementary Materials clinical outcomes, such as recurrent thromboembolism or bleeding events remains limited. We observed the greatest Table 1: Mean, median, and range of levels. Table 2: Per- use of these drug levels in certain clinical scenarios for centage of levels in and out of range. Figure 1: Rivaroxaban acutely hospitalized patients at high risk for bleeding due to levels with a 20 mg daily dose. Figure 2: Apixaban levels in all old age or renal dysfunction. Future studies are necessary in doses. Figure 3: Apixaban DOAC levels plotted against renal these specifc clinical scenarios or when there may be function. Figure 4: Rivaroxaban DOAC levels plotted against concern for unpredictable pharmacokinetics to better renal function. (Supplementary Materials) predict the safety and tolerability of a DOAC. In addition, for those patients presenting to the hospital with bleeding, References a DOAC-specifc level may help predict the need for he- mostatic or reversal agents. As DOACs have overtaken [1] S. Schulman, C. Kearon, A. K. 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Advances in Hematology – Hindawi Publishing Corporation

Published: Feb 22, 2023

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