Conference Report Published by CareFusion Center for Safety and Clinical Excellence
Figure. Unfractionated Heparin: Monitoring
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- Table. Unfractionated Heparin: Dosing
- Weight-based heparin protocol
- Table 1. Weight-based Protocol 2
- Laboratory test variability
- Table 2. Actin FS: Change in Therapeutic aPTT Range at BGSMC Ther. aPTT Ther. aPTT ratio Year
- Figure 1. Change in aPTT therapeutic range following reagent change at BGSMC
- Pseudo heparin resistance
- Methods Study population
- Adverse and clinical outcomes
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Figure. Unfractionated Heparin: Monitoring Monitoring (aPTT) • Time for no effect from bolus: 6-8 hr • No bolus given: 4-6 hr • Kearon et al Arch Intern Med 1998 – Warfarin: INR ↑ 1.0 = ~ 16 sec aPTT ↑ • Monitoring Xa ? 03-07 in DVT – Double Lumen Catheter Draw
Is a bolus needed? How much? • 50-80 units/Kg • 2-3,000 units max • Stroke: None • ACS: 1 units/Kg • LMWH on board • INR > 2 Maintenance Dosing: units/Kg • ACS: 12 units/Kg/hr • Stroke: 15 units/Kg/hr • DVT/PE: 18 units/Kg/hr • Prophylaxis Time aPTT
How many protocols? • ECMO
• Dialysis/CRRT • Pediatrics/Neonates • CT surgery
Executive Summary Conference Report
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ratory testing, standardizing the dosing and monitoring heparin therapy and the method by which the standardized approach is made available to clinician prescribing and moni- toring therapy. Addressing these issues by involving clinicians with knowledge of the laboratory and clinical aspects of heparin therapy can improve treatment outcomes for patients receiving this high-risk medication.
1. Raschke RA, Reilly BM, Guidry JR, et al. The weight- based dosing nomogram compared with a “standard care” nomogram. A randomized controlled trial. Ann Intern Med 1993;119:874-1. 2. Hull RD, Raskob GE, Brant RF, et al. Relation between the time to achieve the lower limit of the APTT thera- peutic range and recurrent venous thromboembolism during heparin treatment for deep vein thrombosis. Arch Intern Med 1997 Dec 8-22;157(22):2562-8. 3. Anand S, Ginsberg JS, Kearon C, et al. The relation between the activated partial thromboplastin time response and recurrence in patients with venous thrombosis treated with continuous intravenous hepa- rin. Arch Intern Med 1996 Aug 12-26;156(15):1677-81. 4. Anand SS, Bates S, Ginsberg JS, et al. Recurrent venous thrombosis and heparin therapy: an evaluation of the importance of early activated partial thromboplastin times. Arch Intern Med 1999 Sep 27;159(17):2029 5. Owings J, Bagley M, Gosselin R, et al. Effect of critical injury on plasma antithrombin activity: low antithrom- bin levels are associated with thromboembolic compli- cations. J Trauma 1996 Sep;41(3):396-405 6. Bond CA, Raehl CL. Pharmacist-provided anticoagula- tion management in United States hospitals: death rates, length of stay, Medicare charges, bleeding complications and transfusions. Pharmacother 2004 Aug;24(8):953-63.
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Executive Summary Conference Report 9th Invited Conference: Improving Heparin Safety PROCEEDINGS Errors involving treatment with unfrac- tionated heparin (UFH) are among the most common and serious in clinical practice. Some recent examples witnessed by the author include administering heparin in response to an order for a Hespan® (hetastarch) bolus, giving therapeutic doses of heparin and enoxaparin simultaneously and administer- ing heparin to a patient with known heparin- induced thrombocytopenia. Practice variability Unnecessary variation in heparin dos- ing is a less dramatic but more pervasive type of error that occurs when protocols for heparin management are not used. Studies have shown that attaining a therapeutic aPTT within 24 hours significantly reduces the risk for recurrent venous thromboembo- lism (VTE), yet non-protocol-driven practice achieves this outcome only 37% of the time 1 .
ment of heparin in the treatment of VTE, ini- tial heparin infusion rates for a 70-kg patient ranged from 500 to 1500 units/hr (7 to 21 units/Kg/hr). Only half of the respondents said they would administer another bolus dose and increase the heparin infusion rate in response to subtherapeutic aPTT values. The survey showed wide variability in aPTT therapeutic ranges, which were not based on valid calculation in the coagulation labora- tory 3
in physician practices increase opportunities for errors in aPTT interpretation and heparin dosing. To reduce this unnecessary and del- eterious variability, a weight-based heparin protocol was developed (Table 1) 2 . Weight-based heparin protocol A randomized, controlled trial (RCT) was conducted at three hospitals that included 115 patients receiving therapeutic-dose hep- Key points • Serious medication errors related to the administration of heparin are common in clinical practice. • Correctly dosing heparin to attain a therapeutic activated partial thromboplastin time (aPTT) within 24 hours significantly reduces the risk for recurrent venous thromboembolism (VTE), yet without the use of a standardized protocol, this outcome is achieved only 37% of the time. • Use of a weight-based heparin protocol significantly increased the percent of patients that reached the therapeutic aPTT threshold within 24 hours and significantly reduced the risk of recurrent VTE. • The sensitivity of aPTT testing devices can vary greatly among testing instruments, reagents, and even reagent lots. • Failure to account for variable sensitivity in aPTT can lead to systematic over- or underdosing of heparin. • The therapeutic aPTT range should be calculated at each institution using the recommended methodology and updated whenever the reagent or lot of reagent is changed. Venous Thromboembolism: Improving Safety and Outcomes of Heparin Therapy Robert Raschke, MD, MS, Director, Critical Care Services, Banner Good Samaritan Medical Center, Phoenix, AZ
• Initial: 80 units/Kg bolus, 18 units/Kg/hr • aPTT value:
1.2 x control bolus, ↑ 4 units/Kg/hr 1.2 - 1.5 bolus, ↑ 2 units/Kg/hr 1.5 - 2.3 no change 2.3 - 3.0 ↓ 2 units/Kg/hr > 3.0 hold 1 hr, ↓ 3 units/Kg/hr
Executive Summary Conference Report
32 9th Invited Conference: Improving Heparin Safety
arin. A standard-care protocol was compared to a weight-based protocol. The weight-based protocol started heparin treatment with a bolus dose of 80 units/Kg and an infusion of 18 units/Kg/hour. Use of the weight-based protocol increased the percent of patients that reached the therapeutic aPTT threshold within 24 hours from 77% to 97% (p=0.002) and significantly reduced the risk of recurrent VTE (RR 0.2, p=0.02) 2 . Laboratory test variability The ability to generalize the weight-based protocol in other institutions was hindered by variability in laboratory methodology used to measure the aPTT. Many different aPTT thromboplastin reagents and instruments are in use in the United States. Each has a unique sensitivity to the effect of heparin (akin to the different sensitivities of prothombin time reagents that necessitate calculation of the INR). Thus, in one hospital a sample might be interpreted as subtherapeutic and the heparin dose increased, and in another hospital the same sample might be interpreted as supra- therapeutic and the heparin dose decreased. Even when a single reagent is used, clin- ically significant changes in the sensitivity can occur from lot to lot. The responsiveness of different lots of the same thromboplas- tin reagent used at BGSMC varied over time (Table 2, Figure 1). If this variable respon- siveness were unaccounted for in calculation of the aPTT therapeutic range, systematic errors would occur in which large numbers of patients would be either under- or over- dosed with heparin, depending on whether the reagent were more or less responsive. The use of aPTT ratios (such as 1.5-2.5 times control) does not ameliorate this prob- lem. Studies have shown that aPTT therapeu- tic ratios vary from 1.6-2.7 times control to 3.7-6.2 times control when the therapeutic range is appropriately determined by anti-Xa measurement 4 ,
. Recommendations To account for the unique responsiveness of the thromboplastin reagent and labora- tory instrumentation, the College of American Pathologists (CAP) and the American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy there- fore recommend that the aPTT therapeutic range be independently validated at each institution. This is accomplished most eas- ily by taking plasma from at least 30 patients receiving heparin therapeutically and simul- taneously measuring anti-Xa heparin levels and aPTT results. The valid aPTT therapeutic range can then be calculated using simple linear regression to correlate the aPTT values with heparin levels of 0.3 to 0.7 anti-Xa units/ mL. Figure 1 shows the results of using this technique when a change in thromboplastin reagent at BGSMC altered the therapeutic range from 45 to 65 seconds to 70 to 105 sec- onds. Failure to recognize this change would have resulted in systematic underdosing of the vast majority of patients receiving intra- venous heparin at that institution. Unfortunately, laboratory-specific valida- tion of the aPTT therapeutic range is often overlooked. A review of 15 RCTs comparing UFH and low-molecular-weight heparin for the treatment of VTE showed that only three studies used appropriately validated aPTT therapeutic ranges and 11 used ranges that were known to be subtherapeutic for the thromboplastin reagents they employed 6 .
ranges was a significant potential source of bias in these studies, since it would be expected to lead to systematic underdosing of heparin. It also demonstrates the perva- siveness of this problem, even in academic medical centers. Table 2. Actin FS: Change in Therapeutic aPTT Range at BGSMC Ther. aPTT Ther. aPTT ratio Year 60-85
1.8-2.5 1989
66-109 2.2-3.6
1990 79-105
2.3-3.0 1991
64-112 2.2-3.9
1997 55-78
1.9-2.7 1998
81-185 2.6-6.0
1998 72-119 to 2.6-4.3 to 3.7-6.2 2001
98-165
Figure 1. Change in aPTT therapeutic range following reagent change at BGSMC 140
120 100
80 60 40 20 0 Anti-Xa heparin level, units/mL aPPT (sec
onds) 0 0.2 0.4 0.6
0.8 1 1.2 1.4 1.6
Actin FSL 1995 - 2002 Actin 1991 - 1995 33
Executive Summary Conference Report 9th Invited Conference: Improving Heparin Safety Pseudo heparin resistance The aPTT therapeutic range may also require recalculation in rare patients with abnormalities such as increased circulating levels of coagulation factor VIII. The plasma of these patients attenuates the sensitivity of the aPTT response, yielding a lower aPTT result at any given plasma heparin concen- tration. Therefore, the patient demonstrates pseudo heparin resistance in which unneces- sarily high doses of heparin may be errone- ously administered to overcome the blunted aPTT response. This diagnosis may be sus- pected when patients require unusually high heparin infusion rates and can be confirmed by comparing a set of the patient’s aPTT values with simultaneous anti-Xa heparin levels. Persistently subtherapeutic aPTTs are observed despite therapeutic or even supra- therapeutic anti-Xa heparin levels. Patients with pseudo heparin resistance can be treat- ed using a protocol based on anti-Xa heparin levels, if that test result is available with acceptable timeliness. Conclusions Implementation of a weight-based hep- arin protocol can be expected to lead to improved intermediate outcomes (such as time until achievement of therapeutic aPTT) and a reduction in recurrent VTE 2 . The use of a protocol with an invalid aPTT therapeutic range may actually be counterproductive. The therapeutic aPTT range at each institu- tion should be calculated by the recommend- ed methodology and updated whenever the reagent or lot of reagent is changed. References 1. Cruickshank MK, Levine MN, Hirsh J, et al. A standard heparin nomogram for the management of heparin therapy. Arch Intern Med 1991;151:333-7. 2. Raschke RA, Reilly BM, Guidry JR, et al. The Weight-based Heparin Dosing Nomogram Compared with a "Standard Care" Nomogram. Ann Internal Med 1993;119(9):874- 81.
3. Reilly B, Raschke R, Sandhya S. et al. Intravenous heparin dosing: patterns and variations in internists’ practices. J Gen Intern Med 1993 Oct;8(10):536-42. 4. Brill-Edwards P, Ginsberg JS, Johnston M, et al. Establishing a therapeutic range for heparin therapy. Ann Intern Med 1993;119:104-9. 5. Bates SM, Weitz JI, Johnston M, et al. Use of a fixed activated partial thromboplastin time ratio to establish a therapeutic range for unfractionated heparin. Arch Intern Med 2001;161:385-91. 6. Raschke R, Hirsh J, Guidry JR. Suboptimal monitoring and dosing of unfractionated heparin in comparative studies with low-molecular-weight heparin. Ann Intern Med 2003;138:720-3. Executive Summary Conference Report
34 9th Invited Conference: Improving Heparin Safety PROCEEDINGS The Epidemiology and Outcomes of Patients Treated With Heparin During Hospitalization Vikas Gupta, PharmD, BCPS, CareFusion, MedMined Services, Birmingham, AL
• Current National Patient Safety Goals call for hospitals to reduce the likelihood of patient harm associated with the use of anticoagulation therapy. • A recent study examined the epidemiology, length of stay and occurrence of bleeding or other complications in non-surgical patients treated with heparin infusions during hospitalization. • A total of 1443 non-surgical cases treated with heparin for at least 24 hours during hospital- ization from January 2004 to June 2007 were analyzed retrospectively. • Based on serum activated partial thromboplastin time (aPTT) results at 6 and 24 hours, cases were categorized as subtherapeutic (< 50 seconds), therapeutic (50-75 seconds), above thera- peutic (76-99 seconds) and supra-therapeutic (≥100 seconds). • One in 3 cases treated with heparin had a subtherapeutic aPTT at 24 hours and these cases had increased hospital length of stay. • Clinicians responsible for assuring anticoagulation safety should incorporate strategies to monitor subtherapeutic aPTT results as diligently as supra-therapeutic results. Introduction Anticoagulant use is a frequent cause of medication errors in hospitalized patients. A review of published studies found that guide- lines recommended by American College of Cardiology/American Heart Association for weight-based heparin therapy are not com- monly used 1,2 . This review also noted a high- er rate of bleeding events in patients who received excess bolus and infusion heparin doses. A study by Fanikos et al. of smart pump technology found that the most common alerts were for underdose (59.8%), followed by overdose (31.3%) 3 . The Joint Commission has issued a Sentinel Event Alert to help hospitals prevent errors associated with commonly used anticoagulants 4 . In this brief report the epidemiology, activated partial thromboplastin time (aPTT) response and outcomes of patients receiving therapeutic doses of heparin are described. Methods Study population Data for this analysis were obtained from the CareFusion Outcomes Research Database, a large, multi-institutional data- base of US acute care hospitals 5 . Data col- lected included patient-level information regarding diagnosis and procedures (all prin- cipal and secondary diagnoses and proce- dure codes), severity of illness on admission, length of hospital stay (LOS), hospital charg- es and clinical variables such as laboratory results and vital signs. Eligible patients were drawn from four hospitals that electronically provided pharmacy orders and laboratory results for an entire hospital stay from January 2004–June 2007. The current study was con- ducted in compliance with the New England Institutional Review Board/Human Subjects Research Committee (Wellesley, MA), fed- eral regulations and the Health Insurance Portability and Accountability Act. All data were de-identified in a manner that did not allow for direct or indirect identification of patient-specific information.
Cases with a heparin order were screened for route and dosing. All cases older than 18 years old receiving intravenous (IV) heparin for more than 24 hours were included in the analysis and were defined as those with a second IV heparin infusion order at least 24 hours after first order, or with an aPTT laboratory order at least 24 hours after first IV heparin infusion order. Cases were grouped based upon their principal discharge diag- nosis (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9- CM]) and further categorized as surgical or medical. aPTT results at 6 hours and at 24 hours post heparin initiation were grouped into the following categories: sub-therapeutic aPTT (< 50 seconds), therapeutic aPTT (50- 75 seconds), above therapeutic aPTT (76-99 seconds) and supra-therapeutic aPTT (≥ 100 seconds). Retrospective analysis identified 1,443 medical cases that received IV heparin infusions as described.
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Executive Summary Conference Report 9th Invited Conference: Improving Heparin Safety Adverse and clinical outcomes Clinical outcomes analyzed included in- hospital mortality, LOS, bleeding or other complications. Bleeding or other complica- tions were identified by the presence of a ICD9 diagnosis code for bleeding at time of admission or by meeting any of the following criteria within 7 days of IV heparin infusion initiation: (1) presence of a ICD9 procedure code for transfusion, (2) thrombocytopenia defined as (a) initial platelet ≥ 150,000 and lowest platelet <150,000, or (b) decrease in platelet count > 50% from baseline; and (3) decreased hemoglobin of ≥ 10% or 4 gm/dL from baseline.
Of the 1,443 medical cases, 216 that did not have an aPTT measured at 24 hours post heparin initiation were excluded. Univariate analysis was performed on the four aPTT cat- egories for mortality, LOS and the presence of bleeding or other complications. Observed and expected mortality and LOS ratios were calculated with previously described predic- tive models that use demography, comor- bidities and laboratory results to stratify risk in the peri-admission period 5 . These models were recalibrated on the study population to account for differences in predicted mortality among disease groups. All statistical analy- ses were performed using Statistical Analysis Software (SAS; version 9.01, SAS Institute Inc., Cary, NC). P values <0.05 were considered statistically 2.17 ^ significant. Yüklə 1 Mb. Dostları ilə paylaş:
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