US Pharm. 2015;40(3):HS26-HS32.
ABSTRACT: Although the introduction of newer anticoagulants has revolutionized the treatment of venous thromboembolism, IV unfractionated heparin (UFH) continues to be widely prescribed in hospitalized patients because of its pharmacokinetic profile. The activated partial thromboplastin time (aPTT) test has been used to monitor outcomes in patients receiving UFH, but significant issues, such as varying aPTT reagents, instrumentation procedures, and interpatient variability, are associated with the test. Antifactor Xa monitoring of patients on continuous IV UFH may better correlate with heparin concentrations, determine therapeutic ranges for aPTT, and result in fewer testing procedures for patients and personnel.
Despite the introduction of newer anticoagulants, IV unfractionated heparin (UFH) is one of the most commonly used parenteral anticoagulants for preventing and treating venous thromboembolism (VTE). The activated partial thromboplastin time (aPTT) test has been used to monitor outcomes in patients receiving UFH, but it has been associated with significant problems, such as varying aPTT reagents, instrumentation procedures, and interpatient variability.1,2 The monitoring of antifactor Xa in patients on continuous IV UFH is being considered by some institutions.
Pharmacology and Clinical Use of UFH
Heparin, a glycosaminoglycan, is housed within secretory granules of mast cells. Commercially available heparin preparations are obtained from bovine lung or porcine intestinal mucosa, which is rich in mast cells. Small amounts of other glycosaminoglycans also may be included in heparin preparations.3,4
The molecular weight (MW) of heparin is highly variable, ranging from 3,000 to 30,000 Da (mean MW 15,000 Da).5-7 Only one-third of heparin molecules administered to a patient produce anticoagulant activity. As a result, the anticoagulant and pharmacokinetic activities of heparin are diverse.8,9
Heparin exerts its effects by combining with circulating antithrombin to enhance the activity of coagulation proteases. Antithrombin inhibits activated coagulation factors in both the common and intrinsic pathways.3,7,8 Binding of heparin with antithrombin occurs through a unique glucosamine unit housed within a pentasaccharide sequence. This leads to a conformational change that accelerates thrombin inhibition. The heparin-antithrombin complex binds to the active center of numerous coagulation enzymes, including factors IIa (thrombin), IXa, Xa, XIa, and XIIa. Of these, thrombin and factor Xa are most responsive, and thrombin’s sensitivity to inhibition is approximately 10 times greater than that of factor Xa.7,8
Heparin molecules with 18 or more saccharides bind the coagulation enzyme and antithrombin simultaneously to exert inhibition of thrombin, which is less important for activated factor Xa inhibition. Heparin prohibits fibrin formation by inactivating thrombin and limits thrombin-induced activation of factors V and VIII. Once the heparin-antithrombin complex binds and inactivates the coagulation enzyme, heparin disassociates and can combine with other circulating antithrombin molecules. The heparin-antithrombin complex is unable to dissolve existing clots, but it prevents activation of coagulation factors that lead to further thrombus enlargement or new thrombus formation.7-10
High-MW heparin molecules with low affinity for antithrombin may confer an increased risk of bleeding by interfering with platelet aggregation. Other effects of heparin independent of anticoagulant activity include increased vessel-wall permeability; suppressed vascular smooth-muscle cell proliferation; and bone loss (suppressed osteoblast formation and promotion of osteoclast activation), which leads to other effects associated with heparin administration.3,8
In 2007 and 2008, heparin was found to be contaminated with oversulfated chondroitin sulfate. The contamination was associated with adverse events (AEs) including hypotension, dyspnea, and nausea during the initial 30 minutes of infusion. Heparin was reformulated with more stringent bioassays and quality-control measures in 2009. The reformulation resulted in a reduction in potency (compared with original preparations) of approximately 10%.11
Heparin is not bioavailable as an oral formulation; therefore, it is administered SC or IV. SC heparin has reduced bioavailability and delayed absorption compared with continuous IV infusion. The anticoagulation effects of SC heparin are usually observed in 1 to 2 hours. Therefore, when immediate therapeutic levels are required, heparin should be administered by continuous IV infusion.3,9,12
Heparin’s anticoagulant activity is diminished as a result of binding to various plasma proteins in the bloodstream, leading to variable responses in patients with thromboembolic disorders, as well as to heparin resistance. Binding to macrophages, platelets, and endothelial cells also affects the pharmacokinetics and associated bleeding risk of heparin. Heparin also binds to and inhibits von Willebrand factor–dependent platelet function.8,12
Clearance and metabolism of therapeutic heparin doses appear to occur primarily in the reticuloendothelial system, which is rapid, saturable, and dose-dependent, resulting in depolymerization of heparin molecules bound to endothelial cell receptors and macrophages. The anticoagulation response to heparin is nonlinear, and there is a disproportionate escalation in anticoagulation effect with increasing dosage. This results in an increased biologic half-life with higher dosages (e.g., the half-life of heparin IV 25 U/kg is 30 minutes, vs. 60 minutes for 100 U/kg). Small quantities of heparin also are cleared through a slower, unsaturable renal mechanism.8,9,12
Therapeutic Indications and Dosing
Heparin is indicated for the treatment and prevention of various thromboembolic disorders, including deep venous thrombosis (DVT), pulmonary embolism (PE), acute coronary syndromes (ACS), coronary bypass, stroke, and stroke prophylaxis in patients with atrial fibrillation and mechanical heart valve replacement.9,12
Heparin’s efficacy is directly tied to dosing. Dosage and route of administration are based upon the indication for anticoagulation and, for parenteral administration, the patient’s response to therapy. SC administration, which is indicated primarily for VTE prophylaxis, is traditionally 5,000 U every 8 to 12 hours. The initial heparin dosage for treatment of VTE (DVT and/or PE) is 80 U/kg bolus administered parenterally, followed by 18 U/kg/h continuous infusion. The American College of Cardiology recommends that anticoagulation with heparin in ACS patients be initiated at 60 to 70 U/kg bolus, followed by 12- to 15-U/kg/h continuous infusion; the dosage may be further reduced when additional agents affecting coagulation are coadministered. In clinical trials, weight-based heparin nomograms increased the number of patients with therapeutic levels in the first 24 hours of therapy and reduced the risk of thromboembolic recurrence.9,12
Patients receiving UFH require close monitoring for AEs such as bleeding and thrombocytopenia. Some tests used to monitor UFH in hospitalized patients are activated partial thromboplastin time (aPTT), antifactor Xa, activated clotting time, and plasma heparin concentration. The activated clotting time test is reserved for patients who receive high doses of UFH when undergoing procedures such as cardiopulmonary bypass and percutaneous coronary intervention.13
aPTT monitoring has been a standard of practice since the 1970s. The variability in outcome results, which is due to physiological and nonphysiological influences on aPTT and lack of a standardized control, has resulted in several institutions moving toward a more effective method of measuring heparin activity in hospitalized patients.14 The need for frequent laboratory monitoring and dosage adjustments based on institution-specific protocols for targeted aPTT has led a number of institutions to consider antifactor Xa monitoring instead of aPTT monitoring in patients on continuous IV UFH.
Two different methods are used to measure heparin concentrations: antifactor Xa functional assay and protamine sulfate titration. The antifactor Xa assay is more widely available and is used in most institutions.13 Antifactor Xa levels are used to monitor both UFH and low-MW (LMW) heparins. Antifactor Xa activity assays are either clot-based or chromogenic, with the latter more often used in practice. In the chromogenic procedure, additional factor Xa is mixed with a chromogenic factor Xa substrate (the amount of excess antithrombin added varies among laboratories). If heparin is present in the specimen, it complexes with antithrombin, inhibiting factor Xa and reducing the amount of color formed. The quantity of chromophore released is inversely proportional to the activity of heparin present, with the results expressed as units/mL of antifactor Xa activity.²
The protamine titration method estimates heparin activity by identifying the lowest titer of protamine that can neutralize heparin-induced clotting prolongation. The American College of Chest Physicians and the College of American Pathologists have agreed that heparin levels based on protamine sulfate titration of 0.2 to 0.4 IU/mL are equivalent to chromogenic heparin antifactor Xa activity levels of 0.3 to 0.7 IU/mL.15 UFH-derived calibration curves determine UFH antifactor Xa activity.
The variability in assays may be attributed to the instrument types on which levels are performed, different manufacturer kits, supplementation of additional antithrombin on certain assays, using heparin from different manufacturers, and different process methods used to create standard calibration curves (which vary among institutions). The therapeutic range for heparin antifactor Xa activity level was established by identifying the antifactor Xa activity level corresponding to a known therapeutic heparin level of 0.2 to 0.4 IU/mL by protamine sulfate titration assay. The limitation of this method is the variability in the antifactor Xa activity assay. The use of LMW heparin curves for measuring the anticoagulant effect of UFH can lead to overestimation of activity. In addition, heparin levels determined by chromogenic heparin antifactor Xa activity are numerically higher than levels determined by protamine titration.15
Instances in which antifactor Xa activity monitoring is favored over aPTT monitoring include heparin resistance, achieving subtherapeutic aPTTs despite dosage increases, and the presence of lupus anticoagulant. When target ranges of antifactor Xa levels are attained early in treatment, a lower level of anticoagulation is seen, along with fewer dosing changes when aPTT targets are at the upper end of the range, which for the treatment of VTE is equivalent to 0.5 to 0.7 U of antifactor Xa activity.15
Clinical Trials Evaluating Antifactor Xa Monitoring
Several hospitals have investigated the efficacy of antifactor Xa heparin assay (HA) monitoring compared with traditional monitoring using aPTT.14,16-19 All patients were given continuous heparin infusions for at least 24 hours, and all protocols were clearly defined. The standard protocol was to monitor at baseline and again every 6 hours after initiation or dosage adjustment until therapeutic levels were attained for two consecutive laboratory values. Individual protocols varied in terms of bolus dose, infusion rate, and method of weight calculation used.
A study by Guervil et al assessed time to therapeutic anticoagulation, whereas a study by Smith and Wheeler evaluated the percentage of patients who were therapeutically anticoagulated after the first antifactor Xa HA and after 24 hours of heparin therapy.14,16 The protocols used weight-based dosing based on actual body weight, although Guervil et al used adjusted body weight in patients weighing more than 125 kg.14,16 Protocols differed in bolus dose administered and infusion rate.14,16
In Guervil et al, the cumulative percentage of patients who achieved therapeutic anticoagulation was significantly higher in patients monitored by antifactor Xa HA than in those monitored by aPTT at 24 hours (50% vs. 22%, odds ratio [OR] 3.5, 95% CI 1.5-8.7) and 48 hours (92% vs. 47%, OR 10.9, 95% CI 3.3-44.2).14 By 72 hours, the difference was nonsignificant.14 Smith and Wheeler had similar results: After 6 hours, 26 of 50 patients had achieved an antifactor Xa HA within target range, and that number increased to 46 patients at 24 hours.16 By 30 hours, 49 of 50 patients had achieved a therapeutic antifactor Xa HA, demonstrating that they were adequately anticoagulated.16
The importance of these findings is underscored by a study conducted by Hull et al.20 This study suggested that patients who achieved a therapeutic monitoring level are less likely to have recurrent thrombotic events than those who are subtherapeutic at 24 hours.20
In an examination of the relationship between antifactor Xa monitoring and aPTT levels, Price et al concluded that most antifactor Xa HA levels and aPTT levels were not paired at therapeutic levels.17 A majority of paired data points had high aPTT levels, compared with corresponding antifactor Xa HA levels. These points were typically found in patients on concomitant warfarin therapy, compared with data points that were therapeutic or points where the antifactor Xa HA was higher relative to the aPTT level. Patients who had a higher antifactor Xa HA compared with the paired aPTT level were at greater risk for major bleed within 21 days and higher 30-day mortality, compared with patients who had both a therapeutic aPTT and an antifactor Xa HA.
Identification of the factors that play a role in appropriate heparin dosing was addressed in a study by Rosborough and Shepherd.18 Multiple factors that vary by patient, including age, height, weight, and gender, were evaluated. Estimation of a patient’s blood volume, combined with the patient’s age, resulted in a more accurate prediction of UFH dosage compared with a weight-based protocol. With the combined protocol, 62% of patients achieved a therapeutic antifactor Xa HA level at 8 hours, versus 37% of patients on the weight-based protocol. The combined protocol was not used with aPTT monitoring, however.18
In a different study, Rosborough assessed the cost of antifactor Xa HA monitoring versus aPTT monitoring.19 Although antifactor Xa HA monitoring cost more per test, significantly fewer tests were required to achieve a therapeutic heparin level. The overall cost was roughly the same for each method, since more aPTT laboratory tests were required before therapeutic levels were reached, even though the test was less expensive.19
Heparin infusions have long been the cornerstone of treatment for PE, DVT, and ACS, owing to the agent’s short half-life and easy reversibility; however, monitoring and adjusting heparin infusions based on institution-specific protocols can result in inconsistent therapeutic levels, since the aPTT does not reliably correlate with heparin’s blood concentrations or anticoagulant effect.21,22 The complexity of monitoring aPTT can be attributed to factor deficiencies, lupus anticoagulant, ongoing inflammatory processes, liver and kidney disease, and certain drug therapies. In clinical practice, aPTT therapeutic ranges at an institution must be established by pairing antifactor Xa levels with aPTT samples from patients receiving heparin and then plotting the values on x- and y-axes using a best-fit regression analysis to determine aPTT ranges correlating with an antifactor Xa range of 0.3 to 0.7 IU/mL.
Given the advent of more specific, reliable, and cost-neutral antifactor Xa level assays, many hospitals are switching to antifactor Xa–based monitoring protocols. Despite the proposed advantages, including faster time to therapeutic range, less need for dose adjustments, fewer laboratory draws, and more consistent therapeutic-range values, outcomes data supporting the use of antifactor Xa protocols are limited. Further research validating the suggested benefits of antifactor Xa monitoring is required. Additionally, standardization of heparin monitoring protocols using antifactor Xa is necessary, along with comparative outcomes data based on selected indications.
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