Evaluation of the use of a heparin dose-response test in dogs to determine the optimal heparin dose during intravascular procedures and assessment of the in vitro heparin response in healthy dogs.

BACKGROUND: No guidelines for administering and monitoring anticoagulants intraprocedurally are currently available in dogs, despite the prevalence of procedures necessitating systemic anticoagulation with heparin. OBJECTIVES: To evaluate an activated clotting time (ACT)-based heparin dose-response (HDR) test to predict the individual required heparin dose in dogs during intravascular procedures, and to investigate both the in vitro heparin - ACT and in vitro heparin - factor anti-Xa activity (anti-Xa) relationships in dogs. METHODS: Blood was collected from eight healthy beagles undergoing a cardiac procedure and utilised to establish baseline ACT and for in vitro evaluation. Subsequently, 100 IU/kg heparin was administered intravenously (IV) and ACT was remeasured (HDR test). The required heparin dose for an ACT target response ≥300 s was calculated for each individual and ACT was remeasured after administration of this dose. For in vitro testing, a serial heparin blood dilution (0-0.5-1-2-4 international unit (IU)/mL) was prepared and ACT and anti-Xa were determined using whole blood and frozen plasma, respectively. RESULTS: The HDR test overestimated the required heparin dose in 3/7 dogs. In vitro, ACT and anti-Xa increased significantly with increasing blood heparin concentration. Heparin - ACT was nonlinear in 4/8 dogs at heparin concentrations >2 IU/mL, whereas heparin - anti-Xa remained linear throughout the tested range. CONCLUSIONS: The HDR test poorly estimated the required heparin dose in dogs. This is most likely attributed to a nonlinear heparin - ACT relationship, as observed in vitro. Anti-Xa is a promising alternative for ACT; however, unavailability as a point-of-care test and lack of in vivo target values restrict its current use.

Performance Assessment of Anti-Xa Assay-Based Heparin Dosing Protocol in Pediatric Patients on Extracorporeal Membrane Oxygenation.

BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) in the postoperative cardiac critical care setting is evolving. Anticoagulation monitoring is among the most challenging aspects of pediatrics. However, there is no consensus on the optimal dosing and monitoring of unfractionated heparin in this setting. To address this, we developed an anti-Xa assay-based protocol derived from the best available clinical and anecdotal evidence of ECMO use and assessed its effectiveness in achieving the anti-Xa assay therapeutic target. METHODS: This prospective single-arm study was conducted in the pediatric carcardiac-surgery intensive care unit of a large tertiary hospital. We used two different anti-Xa assay intensity levels based on the patients' bleeding status. RESULTS: The median patient age was 7 (interquartile range [IQR]: 5-11.25) months, and the median weight was 5.7 (IQR: 3.8-13.82) kg. The median ECMO duration was 6 (IQR: 4.5-7.5) days. The bleeding protocol was used for most patients. Seventy percent achieved the anti-Xa assay therapeutic target during the study period (median: 75.5 h, IQR: 60.5-117.5 h). Hemorrhagic complications were reported in 40% of the patients, and thrombotic complications were reported in 25%. The median length of stay was 37 (IQR: 22-43) days, with a survival-to-discharge rate of 75%. CONCLUSIONS: Despite a failure to achieve the anti-Xa assay target within the first ECMO days, most patients achieved the target by the median ECMO duration. Moreover, using two different anti-Xa assay levels reduced thrombotic complications.

Laboratory Assessment of Unfractionated Heparin (UFH) with Activated Clotting Time (ACT) and Anti-Xa Activity during Peripheral Arterial Angiographic Procedure.

Activated clotting time (ACT) is used in cardiac surgery for monitoring unfractionated heparin (UFH). In endovascular radiology, ACT use is less established. We aimed to test the validity of ACT in UFH monitoring in endovascular radiology. We recruited 15 patients undergoing endovascular radiologic procedure. ACT was measured with ICT Hemochron® device as point-of-care (1) before standard UFH bolus, (2) immediately after the bolus, and in some cases (3) 1 h into the procedure or a combination thereof (altogether 32 measurements). A total of two different cuvettes, ACT-LR and ACT+ were tested. A reference method of chromogenic anti-Xa was used. Blood count, APTT, thrombin time and antithrombin activity were also measured. UFH levels (anti-Xa) varied between 0.3-2.1 IU/mL (median 0.8) and correlated with ACT-LR moderately (R2 = 0.73). The corresponding ACT-LR values were 146-337 s (median 214). ACT-LR and ACT+ measurements correlated only modestly with one another at this lower UFH level, with ACT-LR being more sensitive. Thrombin time and APTT were unmeasurably high after the UFH dose, rendering them of limited use in this indication. We adopted an ACT target of >200-250 s in endovascular radiology based on this study. While ACT correlation with anti-Xa is suboptimal, the readily available point-of-care nature increases its suitability.

Assessment of Anti-Xa activity in patients receiving concomitant apixaban with strong p-glycoprotein inhibitors and statins.

WHAT IS KNOWN AND OBJECTIVES: Although the apixaban Food and Drug Administration (FDA) package insert recommends dose reduction in patients administered dual strong inhibitors of p-glycoprotein (P-gp) and cytochrome P-450 (CYP) 3A4, there are limited published data regarding potential drug-drug interactions between apixaban (Eliquis) and common p-glycoprotein (P-gp) and CYP3A4 inhibitors co-administered with statins. The aim of this study was to investigate the degree of elevation relative to apixaban serum peak and trough concentration after the co-administration of amiodarone, diltiazem and statins (atorvastatin, rosuvastatin and simvastatin). METHODS: Patients prescribed apixaban 5mg twice daily for at least one week were identified from the anticoagulation clinic database and contacted for potential enrolment. A total of 117 volunteers were enrolled with eight excluded due to discontinued use, resulting in 109 volunteers (44 females and 65 males delineated into age groups 40-64 and ≥65 years old) completing the observational study. Fifty-five volunteers were administered apixaban without the P-gp inhibitors amiodarone or diltiazem, with or without statins (atorvastatin, rosuvastatin and simvastatin). Fifty-four volunteers were administered apixaban with either amiodarone or diltiazem, with or without statins (atorvastatin, rosuvastatin or simvastatin). Peak and trough concentrations were assessed for each patient utilizing an apixaban anti-Xa assay. RESULTS: Of the combinations studied, the mean apixaban trough concentration upon co-administration of amiodarone without a statin was elevated compared to apixaban alone (experimental 156.83 +/- 79.59 ng/ml vs. control 104.09 +/- 44.56 ng/ml; p = 0.04). The co-administration of diltiazem and rosuvastatin, and the administration of amiodarone without a statin led to greater than 1.5-fold increase in apixaban concentrations (peak experimental 315.19 +/- 157.53 ng/ml vs control 207.6 +/- 83.38 ng/ml; p = 0.08 and trough experimental 182.03 +/- 95.93 ng/ml vs control 112.32 +/- 37.78 ng/ml; p = 0.17) suggesting the need to assess dose adjustment for patients per the FDA package insert. In addition, the aggregated mean peak (p = 0.0056) and trough (p = 0.0089) elevation of CYP3A4 experimental groups (atorvastatin and simvastatin) co-administered apixaban and diltiazem were statistically significant compared with the aggregated non-CYP3A4 control groups (no statin and rosuvastatin). WHAT IS NEW AND CONCLUSION: Herein, we report novel data regarding peak and trough apixaban concentrations after concomitant administration of P-gp and CYP3A4 inhibitors (amiodarone or diltiazem) co-administered with statins (atorvastatin, rosuvastatin or simvastatin). Providers should consider utilizing the apixaban anti-Xa assay or comparative heparin anti-Xa assay to determine if patients require dose reduction to decrease adverse events in high-risk patients prescribed apixaban and concomitant p-glycoprotein and CYP3A4 inhibitors amiodarone or diltiazem with and without a CYP3A4 or non-3A4 statin.

The ATLANTIC study: Anti-Xa level assessment in trauma intensive care.

OBJECTIVE: To quantify the pharmacodynamic (PD) activity of daily subcutaneous (SC) enoxaparin as venous thromboembolism (VTE) prophylaxis in high-risk trauma patients admitted to the intensive care unit (ICU). METHODS: This was a prospective observational PD study conducted in the ICU of a state-wide major trauma referral centre. The study cohort included adult patients admitted to the ICU with a high risk of VTE, as defined by at least one of the following: age > 40 years, prior VTE, spinal cord injury (SCI), traumatic brain injury (TBI), major venous injury, pelvic fractures, spinal fractures requiring treatment, severe lower limb injuries, and major surgery >2 h in duration. Standard prophylactic enoxaparin dosing was 40 mg SC daily, unless amended by the treating clinician. Plasma anti-Xa activity was measured approximately 60 min before dosing (trough activity), and at 3-5 h after dosing (peak activity). Target peak and trough activity were defined as >0.2 IU/mL and >0.1 IU/mL respectively. Clinical data including the development of VTE and haemorrhagic complications were collected. RESULTS: Twenty-five patients were enrolled. Median [IQR] age, weight, and plasma creatinine were 59 years [36,70], 85 kg [76.5,93.5] and 70µmol/L [60.5,109] respectively. Median APACHE III and Injury Severity Score were 54 [42.5,66.5] and 27 [17,34] respectively. Thirteen patients suffered a TBI, in 12 cases surgery extended beyond two hours, and five patients had spinal fractures requiring treatment. Twenty-two patients received enoxaparin 40 mg SC daily, two 60 mg, and one 20 mg. Median peak and trough anti-Xa activity was 0.21 IU/mL [0.125,0.25] and 0.01 IU/mL [0,0.05] respectively. Twelve (12/25; 48%) patients had low peak activity ≤0.2 IU/mL. Twenty-one (21/23; 91%) patients had low trough activity (≤0.1 IU/mL) and in six (6/23; 26%) cases, these were undetectable. Eight (8/25; 32%) patients had documented VTE of whom seven had low trough activity. There were no major haemorrhagic complications. CONCLUSIONS: In a cohort of high risk critically ill trauma patients receiving daily SC enoxaparin as VTE chemoprophylaxis, measured peak and trough plasma anti-Xa activity was inadequate in a significant proportion. On this basis, further systematic investigation concerning dose optimisation in this patient population appears warranted.

Assessment of venous thromboembolism treatment in patients with cancer on low molecular weight heparin, warfarin, and the direct oral anticoagulants.

BACKGROUND: Direct oral anticoagulants (DOACs) are not recommended for venous thromboembolism (VTE) treatment in patients with cancer because their safety and efficacy have not been compared to low molecular weight heparin (LMWH) in large trials. Routine anti-Xa monitoring in cancer patients on LMWH is also not recommended due to limited data correlating anti-Xa levels and outcomes. OBJECTIVE: Compare the safety and efficacy of DOACs to LMWH and warfarin and assess the relationship of anti-Xa monitoring and outcomes in patients with cancer taking LMWH in an urban university setting. METHODS: This retrospective, cohort study analyzed the recurrence of VTE and number of bleeding events in patients with cancer. RESULTS: There were 131 patients included in the analysis. There was no difference seen in the rate of recurrent VTEs between the LMWH, warfarin and DOAC groups (9.3%, 5.9%, 9.1%, p = 0.89). There was also no difference in the rate of bleeding between groups (10.5%, 14.7%, 9.1%, p = 0.576). There was an increased rate of mortality seen in the LMWH group (26.7% vs. 2.9% vs. 18.2%, p = 0.006). There was no difference seen in recurrent VTE (10.3% vs. 8.5%, p = 0.53) or bleeding (10.3% vs. 10.7%, p = 0.661) between the monitored and unmonitored LMWH patients. CONCLUSION: Results of this analysis suggest DOACs may be as safe and effective as LMWH and warfarin for the treatment of VTE in patients with cancer, and there may be no clinical benefit to routine anti-Xa monitoring in patients on LMWH treatment. However, larger studies are needed to confirm these observations.

Assessment of Heparin Anticoagulation Measured Using i-STAT and Hemochron Activated Clotting Time.

OBJECTIVE: Adequate anticoagulation, measured using activated clotting time (ACT), is important during vascular and cardiac surgeries. Unfractionated heparin is the most common anticoagulant used. The purpose of this analysis was to compare the i-STAT ACT (iACT) to the Hemochron ACT (hACT), both of which were then compared to anti-factor Xa (anti-Xa) assay, a representation of heparin level and activity. DESIGN: Prospective study. SETTING: Tertiary care cardiovascular center. PARTICIPANTS: Eleven consecutive elective adult cardiac surgical patients. INTERVENTIONS: Prior to cardiopulmonary bypass, ACTs were measured using i-STAT and Hemochron technologies and compared to each other and to anti-Xa assay prior to and during a cumulative administration of heparin. Data were compared using bias analyses. MEASUREMENTS AND MAIN RESULTS: Heparin (300 U/kg) was administered in quarterly doses. Coagulation labs were collected prior to and 3 minutes after each quarterly dose of heparin. The baseline ACTs for i-STAT and Hemochron were 147 and 142 seconds, respectively. A significant association was found between iACT and hACT (p = 0.002). The iACT measurements underestimated hACT at ACT levels >180 seconds or anti-Xa levels >0.75 U/mL. No significant difference was found between ACT data at anti-Xa levels <0.5 U/mL. CONCLUSION: There was a good association between the iACT and hACT; however, the 2 tests are not equivalent. Overall, the iACT underestimated the hACT. Agreement between the ACT technologies was good at lower ACTs and anti-Xa levels, but declined with an anti-Xa >0.75 U/mL.

Residual rivaroxaban exposure after discontinuation of anticoagulant therapy in patients undergoing cardiac catheterization.

PURPOSE: Patients treated with direct oral anticoagulants (DOACs) frequently undergo interventional procedures requiring temporary discontinuation of anticoagulant therapy. Little is known about remaining peri-procedural exposure to rivaroxaban in real-world patients. METHODS: Fifty-six patients with rivaroxaban treatment and scheduled cardiac catheterization were included in this prospective, observational, and single-center study. Rivaroxaban concentrations were determined by LC-MS/MS and a chromogenic anti-Xa assay. Population pharmacokinetic modeling was carried out on LC-MS/MS concentration data using NONMEM software, and results were applied to Monte Carlo simulations to predict appropriate rivaroxaban discontinuation intervals. RESULTS: Rivaroxaban concentrations ranged from

Assessment of apixaban plasma levels by laboratory tests: suitability of three anti-Xa assays. A multicentre French GEHT study.

While laboratory monitoring is not required in patients treated with apixaban, a direct factor-Xa inhibitor, assessment of its concentration is useful in some critical situations. However, few data are available on its effect on coagulation tests and on the suitability of anti-Xa assays for its quantification. It was the objective of this study to identify laboratory tests suitable for apixaban concentration assessment. Coagulation tests - PT and aPTT- and anti-Xa assays were performed in apixaban-spiked plasma samples. To evaluate the sensitivity of PT and aPTT to apixaban, we conducted a first monocenter part, with a wide range of concentrations (50-1,000 ng/ml), a large panel of reagents (20 reagents), and two coagulometers (STAR®, Stago and ACL TOP®, IL), and a second multicenter part involving 13 laboratories using either a common PT reagent (RecombiPlastin2G®) or the local PT and aPTT reagents. In the multicentre part, five blinded apixaban-spiked plasma samples (0/100/200/400/800 ng/ml - checked by HPLC-MS/MS) were used; apixaban concentrations were measured with three anti-Xa assays, apixaban calibrators and controls (Stago). PT and aPTT tests using a large panel of reagents displayed a low sensitivity to a wide range of apixaban concentrations. The concentrations to double PT ranged from 400 to >1,000 ng/ml with the 10 reagents. With the three anti-Xa assays, inter-laboratory precision and accuracy were below 11% and 12%, respectively. In conclusion, whereas PT and aPTT tests were not sensitive enough to detect apixaban, the three anti-Xa assays tested using lyophilised apixaban calibrators and controls allowed to reliably quantify a wide range of apixaban concentrations.