Conference Report Published by CareFusion Center for Safety and Clinical Excellence
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- Survey Sample ID Number of Labs submitting results Mean Median CV (%)
- Table 1. 2007 CAP survey of aPTT proficiency testing
- Effect of freezing samples
- Survey Sample ID Number of Labs submitting results Mean Range (U/mL)
- Table 2. 2007 CAP survey of heparin-level proficiency testing Figure representing concurrent testing of samples on two different heparin-assay curves. The dashed line repre
- Bias plot comparison between baseline/UFH anticoagulated samples tested with two different ACT instruments
- Figure 4: Biases among ACT reagents in UFH testing
- Standardized dosing and monitoring guidelines
- Laboratory testing issues
- Laboratory reagent issues
- Electronically available guidelines
- Anticoagulation oversight
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o C for future analysis of new-lot aPTT reagents. 70.0
600 50.0
40.0 30.0
20.0 10.0
0.0 Argatroban concentration, ug/mL 31.1 38.1
65.3 60.9
58.3 54.0
50.7 42.6
63.9 58.5
54.2 51.2
46.6 40.1
35.2 29.3
0.0 0.2
0.4 0.6
0.8 1.0
1.2 1.4
Argatroban-527295 Argatroban-537224
2007 CG2-07 984 67.4s
70s 18.3
45s 104s
2007 CG2-12 1064
34.7s 35 8.8 26s 43s
Sample results of 2007 CAP survey of aPTT proficiency testing. Each data set represents cumulative results for all reporting sites using 8 different reagents and 16 different instrument combinations. Table 1. 2007 CAP survey of aPTT proficiency testing 25
Executive Summary Conference Report 9th Invited Conference: Improving Heparin Safety 9th Invited Conference: Improving Heparin Safety onstrate proficiency compared to its peers for each laboratory test used in patient care. Typically, aPTT proficiency is determined using lyophilized samples distributed by CAP to each clinical laboratory in the U.S. Each labo- ratory tests the blinded samples and submits results to CAP for evaluation. The blinded sam- ples may be normal, contain anticoagulants or have decreased factor levels. In 2007, CAP sent three sets of five blinded samples each to participating laboratories. In the second survey, sample CG2-07 contained “therapeu- tic levels of fractionated heparin,” but 0.5% (5/984) of participating laboratories inter- preted their findings as normal (Table 1). The CAP survey also evaluated heparin- level testing without informing laboratories whether a sample contained UFH or low- molecular-weight heparin (LMWH). The data showed marked differences between results obtained by extrapolating from a UFH or a LMWH curve (Table 2, Figure 3). For laborato- ries using LMWH curves, results ranged from 0.0-0.54; for laboratories using UFH curves, results ranged from 0.0-0.30 (Table 2). In some cases, samples containing no UFH were reported to have UFH levels up to 0.30 Anti- Xa activity. These findings underscore the importance of using the appropriate calibra- tion curve for reporting results and for gener- ating heparin therapeutic ranges. From the CAP survey, it is unclear how the calibration of the heparin test was per- formed, which may account for the bias seen. There have been many reports of variability between reagent methods for determining heparin levels 9-11
. This most likely is due to man- ufacturer-kit differences, including whether the patient’s plasma is supplemented with antithrombin (AT) prior to measuring residual factor Xa. The addition of AT to test plasma may increase the reported heparin level in patients with decreased in-vivo AT levels. Heparin testing is a little more robust than aPTT testing, with few variables that can affect the result. There is better precision with hepa- rin assays and minimal interferences with increased factor activity levels. However, it is important that the correct calibration curve be used for the correct drug monitoring, as there may be an over or underestimation of the heparin levels if an inappropriate curve is used (Figure 3).
CAP allows for freezing of samples from patients on UFH to minimize the difficulty in acquiring an adequate number or UFH patient samples for generating heparin thera- peutic ranges even in smaller institutions. Freezing plasma samples slightly increases the aPTT 12 . A recent internal study at our institution unexpectedly showed that freez- ing was not a viable option. aPTT results from frozen samples averaged 8% higher, but were as much as 85% higher, than results from fresh samples. Overall, 23% of the frozen samples tested higher than the acceptable accuracy threshold (<15%) between fresh and frozen sample results. Using fresh samples for aPTT results, the UFH therapeutic range was 47-65
Survey Sample ID Number of Labs submitting results Mean Range (U/mL) CV (%) Range CV (%) Low 2007 CG2-07 LMWH 195
0.26-0.70 23-34
0.10 1.24
UFH 105
0.38-0.48 13-24
0.20 0.64
2007 CG2-12 LMWH
208 0.07-0.30 40-68 0.0
0.54 UFH
107 0.09-0.19 27-52 0.0
0.30 Samples results of 2007 CAP survey of heparin-level proficiency testing. Each data set represents range results for all reporting sites using 3 different reagents combinations generated from either LMWH or UFH standard curves. Range results are the spread of calculated results between the different reagent combinations. Table 2. 2007 CAP survey of heparin-level proficiency testing Figure representing concurrent testing of samples on two different heparin-assay curves. The dashed line repre- sents heparin-activity (anti-Xa activity) results generated from an UFH curve. The solid line represents testing of the same samples but with heparin-activity results generated using an enoxaparin curve. Figure 3. Differences in testing results using UFH or LMWH curves 1.40
1.20 1.00
0.80 0.60
0.40 0.20
0.00 -0.20
-0.40 Executive Summary Conference Report
26
seconds, while using frozen samples for aPTT results, the therapeutic range was 55-87 sec- onds. This would result in dramatically differ- ent therapeutic ranges, if frozen plasma were used for testing. Laboratory practice requires checking each sample for clots (swirling each sample with applicator sticks to detect fibrin/clot), using a double-spin technique prior to freezing and daily monitoring of centrifuge for platelet- poor plasma generation. Nonetheless, there appeared to be problems with the patient plasma that were not readily apparent during the pre-analytical and analytical phase of test- ing. Filtering plasma collected from selected patients results in multiple filter use, suggest- ing fibrin/platelet aggregate formation. Filters also remove von Willebrand’s factor/Factor VIII complexes, yielding increased aPTTs— another reason why filtering plasma for future aPTT testing is not an acceptable practice. Point of care testing A few point of care (POC) devices are avail- able for monitoring UFH treatment. Most use activated clotting time (ACT), but aPTT and heparin concentrations are also used. Creating a therapeutic range using these devices is more challenging than with laboratory test- ing because of sample type (whole blood used). Test results vary among POC devices and typically do not match laboratory aPTT results, because of differences in sample type, clot detection method and sample-reagent incubation period. ACT is the most commonly used method for POC testing. Differences in methodology include type of activator (kaolin, celite), hepa- rin dosing (low dose 0.1-2.0 units/mL and high dose >2.0 units/mL) and use for either citrated or freshly collected whole blood sam- ples. There are also differences between ACT manufacturers and between ACT cartridge types (Figure 4). UFH anticoagulation may be underestimated if high-dose ACT cartridges are used in patients with lower UFH infusion rates (Figure 5).
Safe and effective anticoagulation therapy requires accurate monitoring, typically using laboratory aPTT testing. Differences among aPTT reagents and instruments, the effects of pre-analytical variables and difficulties in determining the UFH therapeutic range are primary reasons why a strong working relationship between pharmacy and labo- ratory staff should be encouraged. Sharing knowledge about the potential shortcom- ings of UFH therapeutic range determina- tions and coagulation testing, in general, can help reduce the likelihood of harm associated with the use of anticoagulation therapy and improve patient care. Bias plot comparison between baseline/UFH anticoagulated samples tested with two different ACT instruments using 3 different ACT cartridges. This graph demonstrates the biases that exist between ACT reagents. Mean ACT, s ACT Method 1 ACT Method 2 (Low) ACT Method 2 (High)
200
150 100
50 0 -50 -100 -150
-200 0 200 400 600
800 This graph represents the response between ACT cartridges for low-dose UFH anticoagulation. Note the more sensitive response of the low-dose ACT cartridge compared to the high-dose ACT cartridge. Figure 5. ACT cartridges in low-dose UFH anticoagulation monitoring LR-ACT
HR-ACT Heparin concentration, units/mL ACT Unit # 190068019 y = 365.93x÷ 164.29 LR-ACT R² = 0.9832 y = 117.73x÷ 110.58 LR-ACT R² = 0.9945 1800
1600 1400
1200 1000
800 600
400 200
0 0 1 2 3 4 5 27
Executive Summary Conference Report 9th Invited Conference: Improving Heparin Safety References 1. College of American Pathologists Laboratory Accredit- ation Program (LAP) Checklist. Hematology-Coagulation Checklist Revision 09/27/2007. Northfield, IL. 2. Olson JD, Arkin CF, Brandt JT, et al. College of American Pathologists Conference XXXI on laboratory monitor- ing of anticoagulant therapy: laboratory monitoring of unfractionated heparin therapy. Arch Pathol Lab Med 1998;122(9):782-98. 3. Brill-Edwards P, Ginsberg JS, Johnston M, et al. Establishing a therapeutic range for heparin therapy. Ann Intern Med 1993;119(2):104-9. 4. College of American Pathologists Laboratory Accreditation Program (LAP) Checklist. 2007 Participant Survey CG2-B. Pages 6-8. 5. Clinical and Laboratory Standards Institute H21- A4—Collection, Transport, and Processing of Blood Specimens for Testing Plasma-Based Coagulation Assays; Approved Guideline 4th Edition 2003. 6. Kitchen S, Cartwright I, Woods TA, et al. Lipid compo- sition of seven APTT reagents in relation to heparin sensitivity. Br J Haematol 1999;106(3):801-8. 7. Kitchen S, Jennings I, Woods TA, et al. Wide variability in the sensitivity of APTT reagents for monitoring of heparin dosage. J Clin Pathol 1996;49(1):10-4. 8. Hirsh J, Raschke R. Heparin and low-molecular- weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3 Suppl):188S-203S. 9. Kitchen S, Theaker J, Preston FE. Monitoring unfraction- ated heparin therapy: relationship between eight anti- Xa assays and a protamine titration assay. Blood Coagul Fibrinolysis 2000;11(2):137-44. 10. Kovacs MJ, Keeney M. Inter-assay and instru- ment variability of anti-Xa results. Thromb Haemost 2000;84(1):138. 11. Kovacs MJ, Keeney M, MacKinnon K, et al. Three dif- ferent chromogenic methods do not give equivalent anti-Xa levels for patients on therapeutic low molecular weight heparin (dalteparin) or unfractionated heparin. Clin Lab Haematol 1999;21(1):55-60. 12. Adcock D, Kressin D, Marlar RA. The effect of time and temperature variables on routine coagulation tests. Blood Coagul Fibrinolysis 1998;9(6):463-70.
Executive Summary Conference Report
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PROCEEDINGS
• In the treatment of venous thromboembolism (VTE), weight-based dosing that achieves acti- vated partial thromboplastin time (aPTT) values in the target range within 24 hours has been associated with a reduction in recurrent thromboembolism. • The use of heparin dosing and monitoring guidelines usually is necessary to optimize medica- tion safety and therapeutic outcomes. • Problems that can lead to incorrect heparin dosage adjustments include phlebotomy tech- nique, bolus dosing, differences in aPTT reagent sensitivity and confusion in interpreting laboratory results. • Making dosing guidelines available electronically allows for easy access by clinicians and rapid updating to reflect revisions, corrections and follow-up observations. • Standardized procedures to initiating, monitoring and adjusting continuous infusions of heparin and an anticoagulation oversight process can help improve safety and quality of care. Issues in Heparin Management William Dager, PharmD, FCHSP, Pharmacist Specialist, University of California Davis Medical Center, Sacramento, CA Despite the availability of newer paren- teral anticoagulants as preferred alternatives to heparin, a shorter-acting, reversible agent still is needed in certain clinical situations, such as when bleeding risks are high or an invasive procedure requires rapid adjust- ments in anticoagulation intensity. In the treatment of venous thromboembolism (VTE), weight-based dosing that achieves activated partial thromboplastin time (aPTT) values in the target range within 24 hours has been associated with a reduction in recurrent thromboembolism 1 -4
ing is high and thromboembolism low (no acute thromboembolism is present), a lower intensity of anticoagulation (lower value in the aPTT range) and avoidance of bolus dos- ing may be considered.
Usually the use of heparin dosing and monitoring guidelines is necessary to opti- mize medication safety and therapeutic out- comes. Since continuous heparin infusions are used in different clinical settings, different guidelines may be needed to individualize therapy. For example, because of altera- tions in cardiac output and concurrent use of antiplatelet agents, heparin infusion rates may be lower in patients with acute coronary syndrome (ACS) than those being treated for VTE (Table). When treating a patient with a stroke, clinicians may wish to avoid heparin bolus dosing to minimize bleeding risks.
Several factors should be considered when aPTT or activated clotting time (ACT) results are used to help determine heparin dosage adjustments. Drawing serum samples from IV lines increases the risk of hemidilution, which may lead to unexpectedly high aPTT (and INR) values. A large bolus dose of heparin may affect subsequent aPTT values for more than six hours (Figure). For example, an aPTT result for four hours after a 5,000-unit heparin bolus may suggest adequate heparinization, but a subsequent result that reflects only the continuous infusion may be below the target range. Delays in establishing an aPTT in the tar- get range or confusion in interpreting test results can make initiating heparin therapy challenging. Anti-Xa has been suggested as an alternative test; however, potential draw- backs include variability among anti-Xa test- ing methods in reported results or in compar- isons to the aPTT. Anti-Xa testing may reduce variability associated with aPTT but may also reduce accuracy in measuring antithrombotic intensity. The influence of antithrombin (AT) on test results should also be considered. Indirect inhibitors of factor Xa activity such as unfrac- tionated heparin, low-molecular-weight-hep- arin and fondaparinux enhance the activity of AT. Acute reductions in AT resulting from disseminated intravascular coagulation (DIC), large clots, renal disease, trauma, liver disease 29
Executive Summary Conference Report 9th Invited Conference: Improving Heparin Safety or hereditary factors may diminish response to these agents. Low AT levels also have been associated with an increased incidence of thromboembolism 5 . Lack of an aPTT response at heparin rates above 25units/Kg/hr may suggest AT deficiency (or high factor VIII, high fibrinogen). The method by which an assay measures anticoagulation activity should also be considered, e.g., an anti-Xa activity assay that adds AT may not detect low AT activity. Unlike INR for prothrombin ratio, standard- ization of the aPTT has not been achieved, despite several attempts. Different aPTT assays can yield different target ranges for a given infusion of heparin. Changes in an aPTT reagent may necessitate changes in estab- lished dosing and monitoring guidelines. To ensure that clinical practice reflects any such changes, open communication between lab- oratory and clinical staff is essential. Laboratory reagent issues Differences among aPTT reagents should also be considered in determining therapeu- tic ranges and dosing guidelines. For exam- ple, a clinical trial may have been done using a more sensitive aPTT reagent that leads to a higher aPTT target range when calibrated to anti-Xa activity. In clinical practice, use of the higher aPTT target range but a less-sensitive aPTT reagent (lower aPTT results) may lead to systematic overdosing of heparin. Conversely, if a there is a change to a more sensitive reagent, then continued use of previously established guidelines may result in heparin underdosing. Any changes in reagents should be reviewed in advance, new target ranges established and dosing guidelines adjusted.
Maintaining all dosing guidelines in elec- tronically available formats allows the dosing guidelines to be easily accessed by a clinician when ordering a heparin infusion and rap- idly updated to reflect any revisions or correc- tions. The use of pre-printed forms can result in delayed and incomplete implementation of updated guidelines. Electronically avail- able heparin orders can also be adjusted, as necessary, based on follow-up observations.
In addition to standardizing approaches to initiating, monitoring and adjusting con- tinuous infusions of heparin, establishment of an oversight process that involves clinicians with in-depth understanding of anticoagula- tion therapy can help improve outcomes. Individuals involved in oversight may include the responsible physician, bedside nurse, pharmacist and laboratory technician, with one practitioner designated to be responsible for adjusting dosages for patients receiving anticoagulation therapy. Pharmacist-provided anticoagulation management has been asso- ciated with statistically significant reductions in death rates, length of stay, cost of therapy and bleeding complications 6 . Conclusion Given the complexity of intravenous heparin therapy, institutions should consider developing a multidisciplinary approach to anticoagulation management that considers the goals of therapy and addresses the many factors that may influence monitoring, dos- age adjustments and eventual treatment out- comes. These factors include variability in the laboratory testing used to monitor heparin, the appropriate use of the results from labo-
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